Heterocyclic inhibitors of MEK and methods of use thereof

ABSTRACT

Disclosed are compounds of the Formula I  
                 
 
and pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 7 , R 8 , R 9  and R 10 , W and Y are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a series of novel heterocyclic compounds thatare useful in the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

2. Description of the state of the art

Cell signaling through growth factor receptors and protein kinases is animportant regulator of cell growth, proliferation and differentiation.In normal cell growth, growth factors, through receptor activation (i.e.PDGF or EGF and others), activate MAP kinase pathways. One of the mostimportant and most well understood MAP kinase pathways involved innormal and uncontrolled cell growth is the Ras/Raf kinase pathway.Active GTP-bound Ras results in the activation and indirectphosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 on twoserine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahnet al., Methods in Enzymology, 2001, 332, 417-431). Activated MEK thenphosphorylates its only known substrates, the MAP kinases, ERK1 and 2.ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 andT183 for ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417-431).Phosphorylated ERK dimerizes and then translocates to the nucleus whereit accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). In thenucleus, ERK is involved in several important cellular functions,including but not limited to nuclear transport, signal transduction, DNArepair, nucleosome assembly and translocation, and mRNA processing andtranslation (Ahn et al., Molecular Cell, 2000, 6, 1343-1354). Overall,treatment of cells with growth factors leads to the activation of ERK1and 2 which results in proliferation and, in some cases, differentiation(Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

In proliferative diseases, genetic mutations and/or overexpression ofthe growth factor receptors, downstream signaling proteins, or proteinkinases involved in the ERK kinase pathway lead to uncontrolled cellproliferation and, eventually, tumor formation. For example, somecancers contain mutations which result in the continuous activation ofthis pathway due to continuous production of growth factors. Othermutations can lead to defects in the deactivation of the activatedGTP-bound Ras complex, again resulting in activation of the MAP kinasepathway. Mutated, oncogenic forms of Ras are found in 50% of colonand >90% pancreatic cancers as well as many others types of cancers(Kohl et al., Science, 1993, 260, 1834-1837). Recently, bRaf mutationshave been identified in more than 60% of malignant melanoma (Davies, H.et al., Nature, 2002, 417, 949-954). These mutations in bRaf result in aconstitutively active MAP kinase cascade. Studies of primary tumorsamples and cell lines have also shown constitutive or overactivation ofthe MAP kinase pathway in cancers of pancreas, colon, lung, ovary andkidney (Hoshino, R. et al, Oncogene, 1999, 18, 813-822). Hence, there isa strong correlation between cancers and an overactive MAP kinasepathway resulting from genetic mutations.

As constitutive or overactivation of MAP kinase cascade plays a pivotalrole in cell proliferation and differentiation, inhibition of thispathway is believed to be beneficial in hyperproliferative diseases. MEKis a key player in this pathway as it is downstream of Ras and Raf.Additionally, it is an attractive therapeutic target because the onlyknown substrates for MEK phosphorylation are the MAP kinases, ERK1 and2. Inhibition of MEK has been shown to have potential therapeuticbenefit in several studies. For example, small molecule MEK inhibitorshave been shown to inhibit human tumor growth in nude mouse xenografts,(Sebolt-Leopold et al., Nature-Medicine, 1999, 5 (7), 810-816; Trachetet al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H., IBC 2^(nd)International Conference of Protein Kinases, Sep. 9-10, 2002), blockstatic allodynia in animals (WO 01/05390 published Jan. 25, 2001) andinhibit growth of acute myeloid leukemia cells (Milella et al., J. Clin.Invest., 2001, 108 (6), 851-859).

Small molecule inhibitors of MEK have been disclosed. At least thirteenpatent applications have appeared in the last several years: U.S. Pat.No. 5,525,625 filed Jan. 24, 1995; WO 98/43960 published Oct. 8, 1998;WO 99/01421 published Jan. 14, 1999; WO 99/01426 published Jan. 14,1999; WO 00/41505 published Jul. 20, 2000; WO 00/42002 published Jul.20, 2000; WO 00/42003 published Jul. 20, 2000; WO 00/41994 publishedJul. 20, 2000; WO 00/42022 published Jul. 20, 2000; WO 00/42029published Jul. 20, 2000; WO 00/68201 published Nov. 16, 2000; WO01/68619 published Sep. 20, 2001; and WO 02/06213 published Jan. 24,2002.

SUMMARY OF THE INVENTION

This invention provides for novel heterocyclic compounds, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of hyperproliferative diseases. Specifically, oneaspect of the present invention relates to compounds of Formula I thatact as MEK inhibitors. Also provided is a method for treatment ofcancer. Also provided are formulations containing compounds of Formula Iand methods of using the compounds to treat a patient in need thereof.In addition, there are described processes for preparing the inhibitorycompounds of Formula I.

Accordingly, the present invention provides compounds of the Formula I:

-   -   and pharmaceutically accepted salts, prodrugs and solvates        thereof, where:

R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR³,—C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —R³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate,or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

-   -   or R³ and R⁴ together with the atom to which they are attached        form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic        ring, wherein any of said carbocyclic, heteroaryl or        heterocyclic rings are optionally substituted with one or more        groups independently selected from halogen, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,        —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′,        —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,        —NR′C(O)NR′R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R′, R″ and R′″ independently are hydrogen, lower alkyl, lower        alkenyl, aryl and arylalkyl, and R“ ” is lower alkyl, lower        alkenyl, aryl and arylalkyl, or any two of R′, R″, R′″ or R“ ”        together with the atom to which they are attached form a 4 to 10        membered carbocyclic, heteroaryl or heterocyclic ring, wherein        any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings,        heteroaryl rings or heterocyclic rings are optionally        substituted with one or more groups independently selected from        halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or    -   R⁴ and R⁵ together with the atom to which they are attached form        a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring,        wherein said alkyl or any of said carbocyclic, heteroaryl and        heterocyclic rings are optionally substituted with one or more        groups independently selected from halogen, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,        —NR′SO₂R″″, —SO₂NR′R″, —C(O)R″″, —C(O)OR′, —OC(O)R′,        —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,        —NR′C(O)NR″R′″, —NR′C(NCN)N″R′″, —OR′, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,        heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and        heterocyclylalkyl portions are optionally substituted with one        or more groups independently selected from oxo, halogen, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′,        —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R′,        —NR′C(O)NR″R″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,        —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀        alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) and        CR³OR³ wherein any of said heteroaryl, heterocyclyl, —C(O)OR³,        —C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),        —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl) and        —C(O)(heterocyclyl), CR³OR³ are optionally substituted with one        or more groups independently selected from —NR³R⁴, —OR³, —R²,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein any of        said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are        optionally substituted with 1 or more groups independently        selected from —NR³R⁴ and —OR³;    -   m is 0, 1, 2, 3, 4 or 5;    -   j is 1 or 2; and    -   Y is a linker.

In another embodiment, this invention relates to compounds of thegeneral Formula II:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above, and

-   -   R¹¹ is hydrogen, halogen, cyano, nitro, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, —OR³, —C(O)R³,        —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,        —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,        C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),        —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, heterocyclylalkyl,        —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,        —O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,        —O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl,        wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and        heterocyclylalkyl portions are optionally substituted with one        or more groups independently selected from oxo, halogen, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³,        —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,        —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

In another embodiment, this invention relates to compounds of thegeneral Formula III:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above.

In another embodiment, this invention relates to compounds of thegeneral Formula IV:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above.

In another embodiment, this invention relates to compounds of thegeneral Formula V:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R′, R″, R′″, R″″, W,Y, m and j are as defined above.

In a further aspect the present invention provides compositions thatinhibit MEK comprising compounds of Formulas I-V.

The invention is also directed to pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of compounds of Formula I-V. Methods of making the compounds ofFormula I-V are also described.

In a further aspect the present invention provides a method of using thecompounds of this invention to treat diseases or medical conditionsmediated by MEK. For example, this invention provides a method fortreatment of a hyperproliferative disorder in a mammal comprisingadministrating to said mammal one or more compounds of Formulas I-V or apharmaceutically acceptable salt or prodrug thereof in an amounteffective to treat said hyperproliferative disorder.

In a further aspect the present invention provides treating orpreventing an MEK-mediated condition, comprising administering to ahuman or animal in need thereof a pharmaceutical composition comprisinga compound of Formula I-V or a pharmaceutically-acceptable salt or invivo cleavable prodrug thereof in an amount effective to treat orprevent said MEK-mediated condition.

The inventive compounds may further be used advantageously incombination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions comprising aneffective amount of an agent selected from compounds of Formulas I-V ora pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt thereof.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate non-limiting embodiments of the presentinvention, and together with the description, serve to explain theprinciples of the invention.

In the Figures:

FIG. 1 shows a reaction scheme for the synthesis of compound 10a.

FIG. 2 shows a reaction scheme for the synthesis of compound 12a.

FIG. 3 shows a reaction scheme for the synthesis of compound 13a.

FIG. 4 shows a reaction scheme for the synthesis of compound 12b.

FIG. 5 shows a reaction scheme for the synthesis of compound 19.

FIG. 6 shows a reaction scheme for the synthesis of compound 21.

FIG. 7 shows a reaction scheme for the synthesis of compound 30.

FIG. 8 shows a reaction scheme for the synthesis of compound 31.

FIG. 9 shows a reaction scheme for the synthesis of compound 33a.

FIG. 10 shows a reaction scheme for the synthesis of compounds 36-38.

FIG. 11 shows a reaction scheme for the synthesis of compound 39.

FIG. 12 shows a reaction scheme for the synthesis of compounds 44a and44b.

FIG. 13 shows a reaction scheme for the synthesis of compounds 47a and47b.

FIG. 14 shows a reaction scheme for the synthesis of compounds 53a, 53band 54a.

FIG. 15 shows a reaction scheme for the synthesis of compounds 57a and57b.

FIG. 16 shows a reaction scheme for the synthesis of compound 63.

FIG. 17 shows a reaction scheme for the synthesis of compounds 73a and73b.

FIG. 18 shows a reaction scheme for the synthesis of compound 74.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds of the Formulas I-V and the pharmaceuticallyacceptable salts and prodrugs thereof of this invention are useful inthe treatment of hyperproliferative diseases. Specifically, one aspectthe present invention relates to compounds of Formula I-V that act asMEK inhibitors. In general, one aspect of the invention relates tocompounds having the general Formula I:

-   -   and pharmaceutically accepted salts, prodrugs and solvates        thereof, where:    -   R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen,        cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶,        —OC(O)R³, —NR′SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴,        —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),        —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, heterocyclylalkyl,        —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,        —O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,        —O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl,        wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and        heterocyclylalkyl portions are optionally substituted with one        or more groups independently selected from oxo, halogen, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³,        —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,        —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,        heterocyclylalkyl, phosphate, or an amino acid residue, wherein        any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and        heterocyclylalkyl portions are optionally substituted with one        or more groups independently selected from oxo, halogen, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, C(O)OR′, —OC(O)R′,        —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″,        —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl,        heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and        heterocyclylalkyl,    -   or R³ and R⁴ together with the atom to which they are attached        form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic        ring, wherein any of said carbocyclic, heteroaryl or        heterocyclic rings are optionally substituted with one or more        groups independently selected from halogen, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,        —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″,        —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,        —NR′C(NCN)NR′R′″, —OR′, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R′, R″ and R′″ independently are hydrogen, lower alkyl, lower        alkenyl, aryl and arylalkyl, and R″″ is lower alkyl, lower        alkenyl, aryl and arylalkyl, or any two of R′, R″, R′″ or R″″        together with the atom to which they are attached form a 4 to 10        membered carbocyclic, heteroaryl or heterocyclic ring, wherein        any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings,        heteroaryl rings or heterocyclic rings are optionally        substituted with one or more groups independently selected from        halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R″″, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

-   -   R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,        heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and        heterocyclylalkyl portions are optionally substituted with one        or more groups independently selected from oxo, halogen, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′,        —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R′,        —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,        —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀        alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) and        CR³OR³ wherein any of said heteroaryl, heterocyclyl, —C(O)OR³,        —C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),        —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl) and        —C(O)(heterocyclyl), CR³OR³ are optionally substituted with one        or more groups independently selected from —NR³R⁴, —OR³, —R²,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein any of        said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are        optionally substituted with 1 or more groups independently        selected from —NR³R⁴ and —OR;    -   m is 0, 1, 2, 3, 4 or 5;    -   j is 1 or 2; and    -   Y is a linker.

A “linker” is a molecular entity that connects two or more molecularentities through covalent or non-covalent interactions. Examples oflinkers include, but are not limited to, NR³, O, S, S(O), S(O)₂, C(O),and CH₂, where R³ is as defined above.

FIGS. 1-6 show non-limiting examples of the synthesis of compounds ofthis invention having the general Formula I.

In addition to compounds of the general Formula I, this inventionfurther includes compounds of the general Formula II:

where R¹, R², R³, R⁴, R⁵, R R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above, and

R¹¹ is hydrogen, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³,NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl.

FIGS. 7-13 show non-limiting examples of the synthesis of compounds ofthis invention having the general Formula II. FIG. 18 shows thesynthesis of a phosphate prodrug of a compound having the generalFormula II.

In another embodiment, this invention relates to compounds of thegeneral Formula III:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above.

FIG. 14 shows a non-limiting example of the synthesis of compounds ofthis invention having the general Formula III.

In another embodiment, this invention relates to compounds of thegeneral Formula IV:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R′, R″, R′″, R″″, W, Y, mand j are as defined above.

FIG. 15 shows a non-limiting example of the synthesis of compounds ofthis invention having the general Formula IV.

In another embodiment, this invention relates to compounds of thegeneral Formula V:

-   -   where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R′, R″, R′″,        R″″, W, Y, m and j are as defined above. FIGS. 16-17 show        non-limiting examples of the synthesis of compounds of this        invention having the general Formula V.

The terms “C₁-C₁₀ alkyl”, “alkyl” and “lower alkyl” as used herein referto a saturated linear or branched-chain monovalent hydrocarbon radicalhaving one to ten carbon atoms, wherein the alkyl radical may beoptionally substituted independently with one or more substituentsdescribed below. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, heptyl, octyl, and the like.

The terms “C₂-C₁₀ alkenyl”, “lower alkenyl” and “alkenyl” refer tolinear or branched-chain monovalent hydrocarbon radical having two to 10carbon atoms and at least one double bond, and include, but is notlimited to, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyland the like, wherein the alkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The terms “C₂-C₁₀ alkynyl,” “lower alkynyl” and “alkynyl” refer to alinear or branched monovalent hydrocarbon radical of two to twelvecarbon atoms containing at least one triple bond. Examples include, butare not limited to, ethynyl, propynyl, butynyl, pentyn-2-yl and thelike, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The term “allyl” refers to a radical having the formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein theallyl may be optionally substituted independently with one or moresubstituents described herein.

The terms “carbocycle,” “carbocyclyl,” “cycloalkyl” or “C₃-C₁₀cycloalkyl” refer to saturated or partially unsaturated cyclichydrocarbon radical having from three to ten carbon atoms. The term“cycloalkyl” includes monocyclic and polycyclic (e.g., bicyclic andtricyclic) cycloalkyl structures, wherein the polycyclic structuresoptionally include a saturated or partially unsaturated cycloalkyl fusedto a saturated or partially unsaturated cycloalkyl or heterocycloalkylring or an aryl or heteroaryl ring. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. The cycloalkyl may be optionallysubstituted independently in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The terms “heterocycloalkyl,” “heterocycle” or “hetercyclyl” refer to asaturated or partially unsaturated carbocyclic radical of 3 to 8 ringatoms in which at least one ring atom is a heteroatom selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being C, where oneor more ring atoms may be optionally substituted independently with oneor more substituent described below. The radical may be a carbon radicalor heteroatom radical. The term further includes fused ring systemswhich include a heterocycle fused to an aromatic group.“Heterocycloalkyl” also includes radicals where heterocycle radicals arefused with aromatic or heteroaromatic rings. Examples ofheterocycloalkyl rings include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moietiesare also included within the scope of this definition. The foregoinggroups, as derived from the groups listed above, may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclicgroup wherein 2 ring carbon atoms are substituted with oxo (═O) moietiesis 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such heterocycle groups maybe optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy,trifluoromethyl, aryl, heteroaryl, and hydroxy.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings which includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Examples ofheteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups are optionally mono-, di-, or trisubstituted with,e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl,and hydroxy.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above). Morepreferred arylalkyl radicals are aryl-C₁₋₃-alkyls. Examples includebenzyl, phenylethyl, and the like.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Morepreferred heteroarylalkyl radicals are 5- or 6-memberedheteroaryl-C₁₋₃-alkyls. Examples include, oxazolylmethyl, pyridylethyland the like.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Morepreferred heterocyclylalkyl radicals are 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls. Examples include tetrahydropyranylmethyl.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Morepreferred heterocyclyl radicals are 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls. Examples include cyclopropylmethyl.

The term “Me” means methyl, “Et” means ethyl, “Bu” means butyl and “Ac”means acetyl.

In general, the various moieties or functional groups of the compoundsof Formulas I-V may be optionally substituted by one or moresubstituents. Examples of substituents suitable for purposes of thisinvention include, but are not limited to, oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR′C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, where R³, R⁴, R⁵ and R⁶ are as defined herein.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

In the compounds of the present invention, where terms such as(CR⁴R⁵)_(m) or (CR⁴R⁵)_(t) are used, R⁴ and R⁵ may vary with eachiteration of m or t above 1. For instance, where m or t is 2, the terms(CR⁴R⁵)_(m) or (CR⁴R⁵)_(t) may equal —CH₂CH₂— or—CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)— or any number of similar moieties fallingwithin the scope of the definitions of R⁴ and R⁵.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures and pure enantiomers of the Formulas I-V. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. Enantiomers can be separated by converting theenantiomer mixture into a diastereomeric mixture by reaction with anappropriate optically active compound (e.g., alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition, J. March, John Wiley and Sons, New York, 1992).

This invention also encompasses pharmaceutical compositions containing acompound of Formula I-V and methods of treating proliferative disorders,or abnormal cell growth, by administering compounds of the presentinvention. Compounds of the present invention having free amino, amido,hydroxy or carboxylic groups can be converted into pharmaceuticallyacceptable prodrugs.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, omithineand methionine sulfone. One preferred prodrug of this invention is acompound of Formula I-V covalently joined to a phosphate residue.Another preferred prodrug of this invention is a compound of Formula I-Vcovalently joined to a valine residue.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto phosphate esters, hemisuccinates, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem., 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

In addition, the invention also includes solvates, pharmaceuticallyactive metabolites, and pharmaceutically acceptable salts of compoundsof Formulas I-V.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “pharmaceutically active metabolite” is a pharmacologically activeproduct produced through metabolism in the body of a specified compoundor salt thereof. Metabolites of a compound may be identified usingroutine techniques known in the art and their activities determinedusing tests such as those described herein.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. Various forms of prodrugs are knownin the art. For examples of such prodrug derivatives, see, for example,a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs, ” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32: 692 (1984), each ofwhich is specifically incorporated herein by reference.

A “pharmaceutically acceptable salt” as used herein, unless otherwiseindicated, includes salts that retain the biological effectiveness ofthe free acids and bases of the specified compound and that are notbiologically or otherwise undesirable. A compound of the invention maypossess a sufficiently acidic, a sufficiently basic, or both functionalgroups, and accordingly react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid or aninorganic base, such salts including sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, phosphates, monohydrogenphosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, xylenesulfonates,pheylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates. Since a single compound of the present invention mayinclude more than one acidic or basic moieties, the compounds of thepresent invention may include mono, di or tri-salts in a singlecompound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,particularly an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronicacid or galacturonic acid, an alphahydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Preferredinorganic salts are those formed with alkali and alkaline earth metalssuch as lithium, sodium, potassium, barium and calcium. Preferredorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglusoamine, plus salts formedwith basic amino acids such as glycine, omithine, histidine,phenylglycine, lysine and arginine.

The inventive compounds may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available or can besynthesized using methods known in the art.

Illustrations of the preparation of compounds of the present inventionare shown in Schemes 1-11.

Scheme 1 illustrates one method of preparing compounds of the Formula I.Carboxylic acid 102 can be prepared from arene 101 by deprotonation atlow temperature (−100 to −60° C.) in the appropriate ethereal solventsuch as THF or diethyl ether followed by carbon dioxide quench, whichcan be performed with solid dry ice. The deprotonation can beaccomplished with LDA in THF at −78° C. One quench method comprisesadding the aryllithium THF solution via cannula to a saturated solutionof dry carbon dioxide in THF at −78° C. and then warming to roomtemperature. Aniline 103 can be prepared by deprotonation of anappropriate 2-substituted aniline with KHMDS, LiHMDS, NaHMDS or LDA atlow temperature (−100 to −60° C.) in an appropriate ethereal solventsuch as THF or diethyl ether, followed by addition of carboxylic acid102 and warming to room temperature. In one embodiment, deprotonation isaccomplished with LDA at −78° C. in THF, followed by addition ofcarboxylic acid 102 and warming to room temperature. Ester 104 can beprepared by standard methods including, but not limited to, Fisheresterification (MeOH, H₂SO₄), reaction with TMSCHN₂ or TMSCl in MeOH.Acetylene derivative 105 is prepared by Sonagashria coupling of bromide104 using an appropriatly substituted acetylene, CuI, an amine base,palladium catalyst and organic solvent such as DME, THF, or DMF attemperatures between 25 and 100° C. Suitable palladium catalystsinclude, but are not limited to, PdCl₂(dppf), Pd(Ph₃P)₄, and Pd₂dba₃/dppf. Suitable amine bases include, but are not limited, to Et₃N,Hunig's base, and diisopropyl amine. In one embodiment, the Pd(0)mediated coupling to prepare acetylene 105 is accomplished withPd(PPh₃)₂Cl₂, CuI, diisopropyl amine, and the appropriate substitutedacetylene in THF at room temperature. Hydrolysis of acetylene 105 toprepare ketone 106 can be accomplished by standard methods including butnot limited to H₂SO₄, TFA, trifluorosulfonamide, FeCl₃, or HgSO₄/H₂SO₄.Benzisoxazole 107 can be prepared in a two step procedure from ketone106. Addition of the potassium salt of acetone oxime in suitable organicsolvent such as THF or Et₂O at temperatures ranging from −78 to 5° C. isfollowed by acid catalyzed cyclization. The acetone oxime addition ismost easily performed by addition of a THF solution of ketone 106 to thesalt at 0° C. The cyclization can be accomplished with a variety ofacidic aqueous conditions at a range of temperatures. In one embodimentcyclization is accomplished by treatment of theisopropylideneaminooxybenzoic acid methyl ester with 5% aqueous HCl inMeOH at reflux. Halogenation to form benzisoxazole 108 is accomplishedusing standard procedures such as NCS or NBS in DMF. Hydrolysis of ester108 to form carboxylic acid 109 can be performed under standardconditions. The acid can be converted to hydroxamate 110 or amide 112 bystandard coupling procedures including but not limited to EDCI/HOBt,PyBOP, or DIC and the appropriate hydroxylamine or amine. Alternatively,hydroxamate 110 or amide 112 can be prepared in two steps by initialconversion to the acid chloride by standard methods followed by additionof the hydroxylamine or amine. Acyl sulfonamide 111 can be synthesizedby preparing an activated ester of carboxylic acid 109 followed bytreatment with the appropriate sulfonamide and tertiary amine base in asuitable organic solvent such as THF. In one embodiment, acylsulfonamide 111 is prepared by treatment of carboxylic acid 109 with CDIat elevated temperature (50° C.) in THF followed treatment with theappropriate sulfonamide and DBU.

Scheme 2 illustrates an alternative method for synthesizing compounds ofthe Formula I. Nitrile 113 can be prepared by palladium mediatedcoupling of bromide 104 with zinc cyanide in suitable organic solventsuch as DMA, NMP or DMF at elevated temperatures ranging from 50 to 120°C. Several palladium catalysts may be employed including but not limitedto Pd(PPh₃)₄, PdCl₂(dppf), or Pd₂ dba₃ with ligands such as dppe, dppp,dppf or BINAP. In one embodiment, nitrile 113 is prepared from bromide104 by treatment with zinc cyanide, Pd₂ dba₃, and dppf in NMP at 120° C.Amino benzisoxazole 114 can be prepared in a two step procedure fromnitrile 113 by the addition of the potassium salt of acetone oxime insuitable organic solvent such as THF or Et₂O at temperatures rangingfrom −78 to 5° C. followed by acid catalyzed cyclization. In oneembodiment the acetone oxime addition can be performed by addition of aTHF solution of nitrile 113 to the salt at 0° C. in THF followed bywarming to room temperature. The cyclization can be accomplished under avariety of acidic conditions at a range of temperatures. In oneembodiment the cyclization method comprises treatment of the oximeaddition product in MeOH with 2 M HCl in Et₂O. Halogenation to formbenzisoxazole 115 is accomplished using standard procedures such as NCSor NBS in DMF. Compound 116 is prepared in a two step procedurecomprising hydrolysis of ester 115 under standard conditions to form thecorresponding carboxylic acid, followed by conversion of the carboxylicacid to hydroxamate 116 by standard coupling procedures, including butnot limited, to EDCI/HOBt, PyBOP, or DIC and the appropriatehydroxylamine.

Scheme 3 illustrates one method of synthesizing compounds of the FormulaII. 4,6-Dichloronicotinic acid 118 can be prepared from4,6-dihydroxynicotinic acid ethyl ester 117 in two steps. In the firststep, 4,6-dihydroxynicotinic acid ethyl ester 117 is chlorinated usingan appropriate reagent such as POCl₃, oxalyl chloride or thionylchloride. In one embodiment, chlorination is accomplished with POCl₃ andEt₃N at elevated temperatures. Hydrolysis of the resulting dichloroethylester to provide compound 118 can be performed under standardconditions. Aniline 119 can be prepared by deprotonation of the properlysubstituted aniline with KHMDS, LiHMDS, NaHMDS or LDA at low temperature(−100 to −60° C.) in appropriate ethereal solvent such as THF or diethylether followed by addition of carboxylic acid 118 and warming to roomtemperature. In one embodiment, deprotonation is accomplished withLiHMDS at −78° C. in THF, followed by addition of carboxylic acid 118and warming to room temperature. Amino pyridine 120 is prepared in threesteps from aniline 119. In the first step, the tert-butyl ester isprepared by treating the acid 119 with2-tert-butyl-1,3-diisopropylisourea in THF at temperatures ranging from25 to 75° C. In the second step, sodium azide is added to the tert-butylester in DMF at 80° C. The amino pyridine 120 is prepared by reductionof the azide under standard conditions including but not limited to Zndust/AcOH, Pt/C or PtO₂ in the presence of H₂ gas, Ph₃P or SnCl₂/MeOH.In one embodiment, the azide reduction is accomplished by treatment withZn dust in a mixture of methylene chloride and acetic acid. Imidazopyridine 121 where Z=F is prepared in two steps from amino pyridine 120.In the first step, fluorination is accomplished by treatment of theamino pyridine 120 with SELECTFLUOR™ in a mixture of MeOH and water orpH 7 phosphate buffer. Cyclization to form imidazo pyridine 121 (Z=H orF) can be accomplished by treatment with chloro or bromo acetaldehyde insuitable organic solvent such as DMF or EtOH at elevated temperatures(50 to 120° C.). In one embodiment, cyclization is realized by treatmentwith chloroacetaldehyde in EtOH at 70° C. Alternatively, aniline 119 canbe converted to dichloroester 122 in two steps. In the first step,chlorination is performed under standard conditions such as NCS in DMF.In the second step, esterification can be achieved by standard methodsincluding but not limited to Fisher esterification (MeOH, H₂SO₄),reaction with TMSCHN₂ or TMSCl in MeOH. Aminopyridine 123 can beprepared as described above for aminopyridine 120 with the exceptionthat the sodium azide addition can be accomplished at room temperature.Cyclization (achieved as described above for imidazopyridine 121)followed by standard basic saponification gives imidazo pyridine 124.Hydroxamate 125 can be prepared from either imidazo pyridine 121 or 124using standard coupling procedures including but not limited toEDCI/HOBt, PyBOP, or DIC and the appropriate hydroxylamine.Alternatively, hydroxamate 125 can be prepared in two steps by initialconversion to the acid chloride by standard methods followed by additionof the hydroxylamine.

Scheme 4 illustrates an alternative method of preparing compounds ofFormula II. An appropriately functionalized 2-aminopyridine 126 in asuitable organic solvent such as dichloromethane or dichloroethane isreacted with a Lewis acid such as zinc bromide and condensation product(127) as disclosed by Katritzky et al. (J. Org. Chem., 2003, 68,4935-4937: J. Org. Chem., 1990, 55, 3209-3213) to provide the3-dialkyamino-imidazo[1,2-a]pyridine ring system 128. Condensationproducts 127 (i.e., condensation of a glyoxal, benzotriazole and asecondary amine) can be generated using benzotriazole, glyoxal and anyappropriate secondary amine including, but not limited to dimethylamine,diethylamine, pyrrolidine, piperidine, morpholine, 1-methylpiperazine,N-methyl allylamine, diallyamine, and N-methyl benzylamine. The ester128 is hydrolyzed by standard saponification methods, and the resultingacid can be converted to hydroxamate 129 by standard coupling proceduresincluding but not limited to EDCI/HOBt, PyBOP, or DIC and theappropriate hydroxylamine. Alternatively, hydroxamate 129 can beprepared in two steps by initial conversion of the carboxylic acid tothe acid chloride or activated ester by standard methods followed byaddition of the hydroxylamine.

Scheme 5 illustrates an alternative method of preparing compounds of theFormula II. The preparation of 3-aminomethyl imidazo[1,2-a]pyridines 131using the modified Mannich reaction procedure developed by Kercher etal. (manuscript in preparation) is illustrated. The reaction isgenerally carried out by combining 37% aqueous formaldehyde and asuitable amine in 6:1 acetonitrile/water. Several secondary amines canbe employed including but not limited to pyrrolidine, piperadine,morpholine, dimethylamine, N—BOC-piperazine and 1-methylpiperazine. Thesolution of amine and formaldehyde is stirred for approximately half anhour after which time scandium triflate and the appropriateimidazo[1,2-a]pyridine 130 are sequentially added. The Mannich reactionis preferentially catalyzed by a group IIIA lanthanide triflate,preferably scandium triflate, though alternatively it may be performedusing an excess of protic acid (AcOH or HCl) or elevated temperatures.

Scheme 6 illustrates an alternative method of preparing compounds ofFormula II. In Scheme 6, the preparation of 3-aminomethylimidazo[1,2-a]pyridines 134 via reductive alkylation is illustrated. Instep 1, the 3-aminomethyl imidazo[1,2-a]pyridine 133 is prepared fromthe appropriate 3-formyl-imidazo[1,2-a]pyridine 132 and a suitable amineusing standard reduction methods such as Na(CN)BH₃, Na(OAc)₃BH,NMe₄BH(OAc)₃ with or without the addition of acetic acid in a suitablenonreactive organic solvent such as methylene chloride, acetonitrile ortetrahydrofuran. The reductive amination is generally accomplished bytreatment of the aldehyde derivative 132 with the amine and acetic acidin tetrahydrofuran at room temperature followed by the addition ofNa(OAc)₃BH. In cases where R″=H, the corresponding secondary amine 133can optionally be protected, for example with an acid labile protectinggroup such as tert-butyl carbamate (BOC) to facilitate handling insubsequent steps. In step 2, the ester is hydrolyzed by standardsaponification methods, and the resulting acid can be converted tohydroxamate 134 by standard coupling procedures including but notlimited to EDCl/HOBt, PyBOP, or DIC and the appropriate hydroxylamine.Alternatively, hydroxamate 134 can be prepared in two steps by initialconversion of the carboxylic acid to the acid chloride or activatedester by standard methods followed by addition of the hydroxylamine.Protecting groups, if present, are removed after coupling.

Scheme 7 illustrates one method of preparing compounds of Formula III.In Scheme 7 the preparation of 3-alkyl-[1,2,4]triazolo[4,3-a]pyridinederivatives is illustrated. Compound 136 is prepared from compound 135in a two step process. A suitably functionalized 2-chloropyridinederivative 135 is converted to the 2-hydrazinopyridine by reaction withhydrazine. The reaction is generally accomplished by reaction ofhydrazine with 2-chloropyridine derivative 135 in an unreactive organicsolvent such as DMF or DMA at elevated temperature (50 to 100° C.). The2-hydrazinopyridine is then acylated with the appropriate carboxylicacid halide such as fluoride, chloride or bromide, or the appropriatecarboxylic acid anhydride or mixed anhydride in a suitable unreactiveorganic solvent such as dichloromethane, and in the presence of asuitable base such as triethylamine, diisopropylethylamine or pyridine,to provide intermediate 136. Acylation of the 2-hydrazinopyridine canalternatively be accomplished by standard peptide coupling procedureswith the appropriate carboxylic acid and appropriate coupling reagent,including but not limited to EDCl/HOBt, PyBOP, or DIC. The intermediate136 is converted to 3-alkyl-[1,2,4]triazolo[4,3-a]pyridine 137 bytreatment with an excess of phosphorus oxychloride in refluxingdichloromethane. The ester 137 is hydrolyzed by standard saponificationmethods, and the resulting acid 138 can be converted to hydroxamate 139by standard peptide coupling procedures including but not limited toEDCl/HOBt, PyBOP, or DIC and the appropriate hydroxylamine.Alternatively, hydroxamate 139 can be prepared in two steps by initialconversion of the carboxylic acid to the acid chloride or activatedester by standard methods followed by addition of the hydroxylamine.

Scheme 8 illustrates one method of preparing compounds of the FormulaIV. In Scheme 8, the synthesis of 3-methyl-benzo[c]isoxazole derivativesis illustrated. Compound 141 is prepared from compound 140 in a two stepprocess. Methyl ester 140 is treated with sodium azide in 3:1acetone/water at elevated temperature (reflux) to effect nucleophilicsubstitution. The 4-azido derivative is then isolated and heated inwater at reflux to effect cyclization to the benzo[c]isoxazole ringsystem 141. The ester 141 is hydrolyzed by standard saponificationmethods, and the resulting carboxylic acid can be converted tohydroxamate 142 by standard peptide coupling procedures including butnot limited to EDCl/HOBt, PyBOP, or DIC and the appropriatehydroxylamine. Alternatively, hydroxamate 142 can be prepared in twosteps by initial conversion of the carboxylic acid to the acid chlorideor activated ester by standard methods followed by addition of thehydroxyl amine.

Scheme 9 illustrates one method of preparing compounds of Formula V.2-Chloro-4-methyl-5-nitropyridine 143 can be converted to amino pyridine144 in a three step sequence. In the first step, Sonagashria couplingusing TMS-acetylene, CuI, amine base, palladium catalyst and organicsolvent such as DME, THF, or DMF at temperatures from 25 to 100° C.gives the nitroacetylenic pyridine. Suitable palladium catalystsinclude, but are not limited to, PdCl₂(dppf), Pd(Ph₃P)₄, Pd(PPh₃)₂Cl₂and Pd₂ dba₃/dppf. Suitable amine bases include, but are not limited to,Et₃N, Hunig's base, and diisopropyl amine. The amino pyridine 144 isthen prepared by removal of the TMS group under standard conditions suchas K₂CO₃ in MeOH, followed by reduction of the nitro group using eitherZn dust/AcOH, Fe or SnCl₂/MeOH. For Z=H, amino pyridine 144 is useddirectly in the cyclization reaction. When Z=Cl, aminopyridine 144 ishalogenated under standard conditions with NCS in DMF and then carriedforward to the cyclization. When Z=F, the 2-chloro-3-aminopyridineintermediate is treated with KF, Kryptofix in DMSO to prepare aminopyridine 145. Cyclization to give pyrazolo[1,5-a]pyridine 146 isaccomplished by treating aminopyridine 145 withO-(4-nitrophenyl)-hydroxylamine in a suitable organic solvent such asDMF at room temperature in presence of a base such as K₂CO₃. Carboxylicacid 149 can be prepared, for example, using one the following routes.One route involves palladium mediated cross-coupling with appropriatelysubstituted bromobenzene and amino-pyrazolo[1,5-a]pyridine 146. In thiscase, the cross-coupling can be accomplished with palladium catalyst andorganic solvent such as DME, THF, dioxane, and toluene at temperaturesfrom 60 to 120° C. Suitable palladium catalysts include, but are notlimited to, Pd(OAc)₂, PdCl₂(dppf), Pd₂(bda)₃, and Pd(dba)₂. Suitableligands include, but are not limited to, BINAP, DPPF, and (o-tol)₃P.Suitable amine bases include, but are not limited to, NaOt-Bu, KOt-Bu,and Cs₂CO₃. The second route involves S_(N)Ar reaction withamino-pyrazolo[1,5-a]pyridine 146 and the appropriately substituted2-fluoronitro-benzene. In this case, the coupling can be accomplished bymixing the two components in a suitable organic solvent such as xylenes,toluene, DMSO or DMF at elevated temperatures (80 to 150° C.).Optionally, a base can be employed in the S_(N)Ar coupling such as K₂CO₃or Cs₂CO₃. The carboxylic acid 149 is then prepared by functionalizationof the aromatic ring followed by oxidation. In the first case,functionalization involves halogenation under standard conditions witheither NCS or NBS in DMF. In the second case, functionalization involvesSandmeyer chemistry to convert the nitroarene into the desired arene orarylhalide (nitro group reduction; diazonation; halogentation orprotonation). In both routes, the last step to prepare carboxylic acid149 is oxidation of the toluyl moiety. This can be achieved usingstandard methods including but not limited to KMnO₄, NaOCl/RuCl₃ orNa₂Cr₂O₇/HCl. The resulting carboxylic acid 149 can be converted tohydroxamate 150 by standard peptide coupling procedures including butnot limited to EDCI/HOBt, PyBOP, or DIC and the appropriatehydroxylamine. Alternatively, hydroxamate 150 can be prepared in twosteps by initial conversion of the carboxylic acid to the acid chlorideor activated ester by standard methods followed by addition of thehydroxylamine.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for the treatment of cancer such as brain,lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck,renal, kidney, ovarian, prostate, colorectal, esophageal, testicular,gynecological or thyroid cancer. In another embodiment, saidpharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal which comprises a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. In oneembodiment, said pharmaceutical composition is for treating a diseaseselected from the group consisting of tumor angiogenesis, chronicinflammatory disease such as rheumatoid arthritis, atherosclerosis,inflammatory bowel disease, skin diseases such as psoriasis, excema, andscleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi'ssarcoma and ovarian, breast, lung, pancreatic, prostate, colon andepidermoid cancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof. Inone embodiment, said method relates to the treatment of cancer such asbrain, lung, squamous cell, bladder, gastic, pancreatic, breast, head,neck, renal, kidney, ovarian, prostate, colorectal, esophageal,testicular, gynecological or thyroid cancer. In another embodiment, saidmethod relates to the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, in combination with an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors,biological response modifiers, anti-hormones, angiogenesis inhibitors,and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyteimplantation in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, excema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs and hydrates of saidcompounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having psoriasis,restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system (e.g., cancer of the thyroid, parathyroid or adrenalglands), sarcomas of soft tissues, cancer of the urethra, cancer of thepenis, prostate cancer, chronic or acute leukemia, solid tumors ofchildhood, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter (e.g., renal cell carcinoma, carcinoma of the renalpelvis), or neoplasms of the central nervous system (e.g., primary CNSlymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a pharmaceutically acceptablesalt or solvate or prodrug thereof, in combination with an amount of achemotherapeutic, wherein the amounts of the compound, salt, solvate, orprodrug, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichmethod comprises administering to the mammal an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt or solvateor prodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation which comprises administering tothe mammal an amount of a compound of the present invention orpharmaceutically acceptable salt or solvate or prodrug thereof, whichamount is effective in sensitizing abnormal cells to treatment withradiation. The amount of the compound, salt, or solvate in this methodcan be determined according to the means for ascertaining effectiveamounts of such compounds described herein.

The invention also relates to a method of and to a pharmaceuticalcomposition of inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, etoricoxib, lumiracoxib and rofecoxib. Examplesof useful matrix metalloprotienase inhibitors are described in WO96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7,1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997),European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29,1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (publishedAug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566(published Jul. 16, 1998), European Patent Publication 606,046(published Jul. 13, 1994), European Patent Publication 931,788(published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21,1999), WO 99/29667 (published Jun. 17, 1999), PCT InternationalApplication No. PCT/IB98/01113 (filed July 21, 1998), European PatentApplication No. 99302232.1 (filed Mar. 25, 1999), Great Britain PatentApplication No. 9912961.1 (filed Jun. 3, 1999), U.S. ProvisionalApplication No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan.19, 1999), and European Patent Publication 780,386 (published Jun. 25,1997), all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth,” as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, forexample, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or overexpression ofa receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/theroine kinase activation occurs.

The term “treating,” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment,” as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the mammal inneed of treatment, but can nevertheless be routinely determined by oneskilled in the art. “Treating” is intended to mean at least themitigation of a disease condition in a mammal, such as a human, that isaffected, at least in part, by the activity of MEK, and includes, but isnot limited to, preventing the disease condition from occurring in amammal, particularly when the mammal is found to be predisposed tohaving the disease condition but has not yet been diagnosed as havingit; modulating and/or inhibiting the disease condition; and/oralleviating the disease condition.

In order to use a compound of the Formula I-V or a pharmaceuticallyacceptable salt or prodrug thereof, for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition that comprisesa compound of the Formula I-V, or a pharmaceutically acceptable salt orprodrug thereof, as defined hereinbefore in association with apharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing). For example, compositionsintended for oral use may contain, for example, one or more coloring,sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990, which is specifically incorporated hereinby reference.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 0.5 to about 35 mg/kg/day, in single ordivided doses. For a 70 kg human, this would amount to about 0.05 to 7g/day, preferably about 0.05 to about 2.5 g/day. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day. For further information on routes of administration and dosageregimes, see Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990, which is specifically incorporated herein by reference.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I-V will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

The compounds of this invention may be used alone in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of MEK. For example, a compound ofthis invention may be applied in combination with one or more otheranti-tumor substances, including, but not limited to, mitotic inhibitorssuch as vinblastine; alkylating agents such as cis-platin, carboplatinand cyclophosphamide; anti-metabolites such as 5-fluorouracil, cytosinearabinside and hydroxyurea; or, for example, one of the preferredanti-metabolites disclosed in European Patent Application No. 239362such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; signal transduction inhibitors, such asagents that can inhibit EGFR (epiderman growth factor receptor)responses, such as EGRF antibodies, EGF anitbodies and molecules thatare EGFR inhibitors such as the compounds ZD-1839 (AstraZeneca) andBIBX-1382 (Boehringer Ingelheim); VEGF inhibitors such as SU-6668 (SugenInc. of South San Francisco, Calif., USA) or the anit-VEGF monoclonalantibody of Genentech, Inc. of South San Francisco, Calif.; cell cycleinhibitors; intercalating antibiotics such as adriamycin and bleomycin;enzymes, for example, interferon; and anti-hormone such asanti-estrogens such as Nolvadex™ (tamoxifen); or, for exampleanti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of treatment.

Although the compounds of Formula I-V are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of MEK.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

The activity of the compounds of the present invention may be determinedby the following procedure. N-terminal 6 His-tagged, constitutivelyactive MEK-1 (2-393) is expressed in E. coli and protein is purified byconventional methods (Ahn et al., Science 1994, 265, 966-970). Theactivity of MEK1 is assessed by measuring the incorporation ofγ-³³P-phosphate from γ-³³P-ATP onto N-terminal His tagged ERK2, which isexpressed in E. coli and is purified by conventional methods, in thepresence of MEK-1. The assay is carried out in 96-well polypropyleneplate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4,10 mM MgCl₂, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mMDTT, 5 nM MEK1, and 1 μM ERK2. Inhibitors are suspended in DMSO, and allreactions, including controls are performed at a final concentration of1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5μCi γ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.Equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP washed off using a Tomtec MACH IIIharvestor. Plates are allowed to air-dry prior to adding 30 μL/well ofPackard Microscint 20, and plates are counted using a Packard TopCount.In this assay, compounds of the invention exhibited an IC₅₀ of less than50 micromolar.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and their pharmaceutically acceptable acid or baseaddition salts or prodrugs thereof. The examples presented below areintended to illustrate particular embodiments of the invention, and arenot intended to limit the scope of the specification or the claims inany way.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other MEK inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),dichloromethane, toluene, dioxane and 1,2-difluoroethane were purchasedfrom Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Bruker instrument operating at 300 MHzor on a Varian instrument operating at 400 MHz. ¹H-NMR spectra wereobtained as CDCl₃ solutions (reported in ppm), using chloroform as thereference standard (7.25 ppm). Other NMR solvents were used as needed.When peak multiplicities are reported, the following abbreviations areused: s (singlet), d (doublet), t (triplet), m (multiplet), br(broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

Example 1

Synthesis of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9a)

The reaction scheme for the synthesis of compound 9a is shown in FIG. 1.

Step A: Preparation of 5-bromo-2,3,4-trifluorobenzoic acid (2): To asolution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) inTHF (120 mL) was added lithium diisopropylamine (2.0 M solution, 21 mL,42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixturewas added to a solution of CO₂ in THF (1 L). The dry-ice bath wasremoved and the reaction mixture stirred overnight at room temperature.The reaction mixture was quenched with 10% aqueous HCl (835 mL),concentrated, and washed with ether (250 mL). The combined organics werewashed with 5% aqueous NaOH (300 mL) and water (100 mL, pH 12). Theaqueous layer was acidified (pH 0) with concentrated HCl. The resultingsuspension was extracted with ether (2×300 mL), dried over MgSO₄,filtered, concentrated under reduced pressure to afford 7.70 g (72%yield) of the desired product (2).

Step B: Preparation of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3): To asolution of lithium diisopropylamine (49.0 mL, 2 M in THF/heptane) inTHF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol) at −78°C. After vigorous stirring for 10 minutes, a solution of5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2 mmol) in THF (60mL) was added. The dry-ice bath was removed and the reaction mixturestirred for 4 hours at room temperature. The mixture was concentrated,treated with 10% aqueous HCl (75 mL), and extracted with EtOAc. Thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated. Purification by trituration with boiling CH₂Cl₂ gave 7.24g (66%) of the desired acid (3) as a yellow solid

Step C: Preparation of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester(4): To a solution of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3) (4.50 g,12.4 mmol) in a 3:1 mixture of THF:MeOH (32 mL) was added(trimethylsilyl)-diazomethane (8.10 ml of a 2 M solution in hexanes) atroom temperature. After stirring for 2 hours, the reaction mixture wasquenched with acetic acid, diluted with EtOAc, and washed with water.The organic layer was dried (MgSO₄) and concentrated under reducedpressure to give 4.35 g (93%) of the desired methyl ester (4).

Step D: Preparation of2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynyl-benzoicacid methyl ester (5): A mixture of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester(4) (101 mg, 0.268 mmol), TMS-acetylene (0.045 mL, 0.31 mmol),Pd(PPh₃)₂Cl₂ (18.7 mg, 0.0261 mmol), CuI (5.1 mg, 0.027 mmol), andi-Pr₂NH (0.075 mL, 0.53 mmol) in THF (1.5 mL) was stirred for 16 hoursat room temperature. The reaction mixture was concentrated under reducedpressure, and diluted with EtOAc. The organic layer was washed withsaturated aqueous NH₄Cl and brine, dried over MgSO₄, and concentrated.Purification by flash column chromatography using the Biotage system(100% hexane to 1% EtOAc in hexane) gave 81.3 mg (77% yield) of thedesired product (5).

Step E: Preparation of5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester(6): A mixture of2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoicacid methyl ester (5) (79.4 mg, 0.20 mmol), HgSO₄ (59.8 mg, 2.0 mmol),and conc. H₂SO₄ (0.02 mL, 0.40 mmol) in 80% aqueous acetone (2.5 mL),were refluxed for 48 hours. The reaction was concentrated under reducedpressure, and diluted with EtOAc. The organic layer was washed withwater and brine, dried over MgSO₄ and concentrated to give 50.1 mg (73%)of the desired product (6).

Step F: Preparation of 6-(2-chlorophenylamino)-7-fluoromethylbenzo[d]isoxazole-5-carboxylic acid methyl ester (7): t-BuOK (0.47mL, 1.0 M in THF) was added to propan-2-one oxime (35 mg, 0.47 mmol).After stirring for 30 minutes, THF (0.5 mL) was added, and the reactionmixture was cooled to −78° C. A solution of5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester(6) (50.0 mg, 0.147 mmol) in THF (1 mL) was added. The reaction mixturewas slowly warmed to 0° C. and stirred for 2 hours. The reaction mixturewas quenched with saturated aqueous NH₄Cl, diluted with EtOAc and water.The aqueous layer was separated and extracted with EtOAc. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated invacuo to give the5-acetyl-2-(2-chloro-phenylamino)-3-fluoro-4-isopropylideneaminooxy-benzoicacid methyl ester. The recovered oxime was suspended in a 1:1 mixture of5% aqueous HCl and MeOH (30 ml) and heated to reflux. After 1 hour, thereaction mixture was cooled to room temperature and diluted with EtOAc.The organic layer was washed with water, dried (MgSO₄) and concentrated.Purification by flash column chromatography using the Biotage system(40% methylene chloride in hexanes) provided 17 mg (35% for two steps)of the desired product (7).

Step G: Preparation of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-benzo[d]isoxazole-5-carboxylicacid methyl ester (8a):6-(2-Chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid methyl ester (7) (18.6 mg, 0.0556 mmol) and N-bromosuccinimide(12.0 mg, 0.0667 mmol) were stirred in DMF (1 mL) for 16 hours. Thereaction mixture was diluted with EtOAc, and washed with water (2×). Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification by flash column chromatography using the Biotage system(10% EtOAc in hexanes) provided 12.6 mg (55%) of the desired product(8a).

Step H: Preparation of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9a): To a solution of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid methyl ester (8a) (200 mg, 0.48 mmol) in THF-water (3 mL/1.5 mL)was added aqueous LiOH (1M, 1.00 mL) at room temperature. After 15hours, the reaction mixture was acidified to pH 1 with aqueous HCl (1M),diluted with water, and extracted with EtOAc/THF. The organic layer waswashed with water, dried over MgSO₄, filtered, and concentrated in vacuoto give 191.5 mg (99%) of the crude acid (9a) which was used withoutfurther purification. MS APCI (−) m/z 397, 399 (M+, Br, Cl pattern)detected: ¹H NMR (400 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.37 (s, 1H), 7.75(s, 1H), 7.42 (d, 1H), 6.97 (t, 1H), 2.60 (s, 3H): ¹⁹F NMR (376 MHz,DMSO-d₆) -140.15 (s, 1F).

Example 2

Synthesis of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid cyclopropylmethoxyamide (10a)

The reaction scheme for the synthesis of compound 10a is shown inFIG. 1. To a solution of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9a) (50.0 mg, 0.125 mmol) in DMF (1 mL) was added HOBt (24.6 mg,0.161 mmol), Et₃N (0.060 mL, 0.43 mmol),O-cyclopropylmethyl-hydroxylamine (15.5 mg, 0.178 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (32.2mg, 0.168 mmol) at room temperature. After 6 days, the reaction mixturewas diluted with EtOAc, washed with saturated aqueous NH₄Cl, brine,saturated aqueous NaHCO₃, and brine. The organic layer was dried overMgSO₄, filtered, concentrated in vacuo, and purified by flash columnchromatography using the Biotage system (0.5% MeOH in CH₂Cl₂) to give27.6 mg (47% yield) of the desired product (10a). MS APCI (−) m/z 466,468 (M+, Br, Cl pattern) detected: ¹H NMR (400 MHz, CD₃OD) δ 7.82 (s,1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 3.73 (d, 2H), 2.60 (s,3H), 1.16 (m, 1H), 0.55 (m, 2H), 0.28 (m, 2H): ¹⁹F NMR (376 MHz,CD₃OD)-140.96 (s, 1F).

Example 3

Synthesis of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (2-hydroxyethoxy)-amide (12a)

The reaction scheme for the synthesis of compound 12a is shown in FIG.2.

Step A: Preparation of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-benzo[d]isoxazole-5-carboxylicacid (2-vinyloxyethoxy)-amide (11a): To a solution of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (10a) (75.2 mg, 0.188 mmol) in DMF (1.5 mL) was added HOBt (38.2mg, 0.249 mmol), Et₃N (0.080 mL, 0.571 mmol),O-(2-vinyloxyethyl)hydroxylamine (28.5 mg, 0.276 mmol), and EDCI (47.2mg, 0.246 mmol) at room temperature. After 6 days, the reaction mixturewas diluted with EtOAc, washed with saturated aqueous NH₄Cl, brine,saturated aqueous NaHCO₃, and brine. The organic layer was dried overMgSO₄, filtered, concentrated in vacuo, and purified by flash columnchromatography using the Biotage system (3% MeOH in CH₂Cl₂) to give 57.8mg (63%) of the desired product (1 la).

Step B: Preparation of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (2-hydroxyethoxy)-amide (12a): A solution of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (2-vinyloxyethoxy)amide (11a) (55.4 mg, 0.114 mmol) and aqueous HCl(1M, 0.23 mL) in EtOH (3 mL) was stirred for 2 hours at roomtemperature. The pH of the reaction mixture was adjusted to 6-7 withaqueous NaOH (2 N). The reaction was diluted with EtOAc. The organiclayer was washed with water, dried over MgSO₄, filtered, andconcentrated in vacuo to give 50.2 mg (96% yield) of the desired product(12a). MS APCI (−) m/z 456, 458 (M+, Br, Cl pattern) detected: ¹H NMR(400 MHz, CD₃OD) δ 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd,1H), 4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): ¹⁹F NMR (376 MHz,CD₃OD)-140.85 (s, 1F).

Example 4

Synthesis ofN-[6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carbonyl]-methanesulfonamide(13a)

The reaction scheme for the synthesis of compound 13a is shown in FIG.3. A mixture of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9a) (41 mg, 0.102 mmol) and carbonyl diimidazole (23 mg, 0.140mmol) in THF (1 mL) was stirred at 50° C. in a sealed tube reactor. Thereaction mixture was cooled to room temperature and methanesulfonamide(17 mg, 0.179 mmol) was added followed by DBU (0.025 ml, 0.164 mmol).After stirring at 50° C. for 1 hour, the reaction mixture was cooled toroom temperature, and diluted with EtOAc. The organic layer was washedwith water, 1N HCl, and brine. The organic layer was dried (MgSO₄) andconcentrated. Purification by flash column chromatography using theBiotage system (7% MeOH in CH₂Cl₂) provided 34 mg (65% yield) of thedesired product (13a). MS APCI (−) m/z 474, 476 (M+, Br, Cl pattern)detected: ¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 7.53 (s, 1H), 7.27 (d,1H), 6.73 (t, 1H), 3.11 (s, 3H), 2.55 (s, 3H): ¹⁹F NMR (376 MHz,CD₃OD)-141.84 (s, 1F).

Example 5

Synthesis of 6-(2,4-dichloro-phenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (9b)

The reaction scheme for the synthesis of compound 9b is shown in FIG. 1.

Step A: Preparation of6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid methyl ester (8b):6-(2-Chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid methyl ester (7) (129 mg, 0.384 mmol) and N-chlorosuccinimide (57mg, 0.421 mmol) were stirred in DMF (5 mL) for 16 hours. ConcentratedHCl (3 μL) was added and the reaction mixture stirred 2 hours. Thereaction mixture was diluted with EtOAc, and washed with water (2×). Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification by flash column chromatography using the Biotage system (5%EtOAc in hexanes) provided 73 mg (52%) the desired product (8b).

Step B: Preparation of6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9b): Compound 9b was prepared according to Step H of Example 1using6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid methyl ester (8b) to provide 68 mg (98% yield) of the desiredproduct (9b). MS APCI (−) m/z 353, 355 (M+, Br, Cl pattern) detected: ¹HNMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.34 (s, 1H), 7.65 (d, 1H), 7.31(dd, 1H), 7.04 (dd, 1H), 2.60 (s, 3H): ¹⁹F NMR (376 MHz, DMSO-d₆)-140.36(s, 1F).

Example 6

Synthesis of6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (2-hydroxyethoxy)amide (12b)

The reaction scheme for the synthesis of compound 12b, as shown in FIG.4, was carried out according to Steps A and B of Example 3 using6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylicacid (9b) as the starting material to provide 29 mg (38% yield for twosteps) of 12b. MS APCI (−) m/z 412, 414 (M+, Br, Cl pattern) detected:¹H NMR (400 MHz, CD₃OD) δ 7.87 (s, 1H), 7.45 (m, 1H), 7.19 (m, 1H), 6.80(m, 1H), 4.02 (t, 2H), 3.75 (t, 2H), 2.60 (s, 3H): ¹⁹F NMR (376 MHz,CD₃OD)-141.05 (s, 1F).

Example 7

Synthesis of3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylicacid (19)

The reaction scheme for the synthesis of compound 19 is shown in FIG. 5.

Step A: Preparation of2-(2-chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl ester(15): A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoicacid methyl ester (14) (3.01 g, 7.99 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf) (93 mg, 0.162 mmol), Pd₂ dba₃ (73 mg, 0.080 mmol) andZn(CN)₂ (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidinone (NMP: 4.5 mL)was heated in a sealed tube reactor. After 20 hours, the reactionmixture was cooled to room temperature, quenched by the addition of 8 mL4:1:4 (volume) mixture of saturated NH₄Cl, concentrated NH₄OH and water,and extracted with a mixture of EtOAc:THF. The combined organic extractswere washed with 4:1:4 (volume) mixture of saturated NH₄Cl, concentratedNH₄OH and water, and brine. The organic layer was dried (MgSO₄) andconcentrated. Purification by flash column chromatography using theBiotage system (twice: 100% hexanes to 35% CH₂Cl₂ in hexanes, then 30%CH₂Cl₂ in hexanes) provided 1.33 g (52%) of the desired product (15).

Step B: Preparation of3-amino-6-(2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylicacid methyl ester (17): t-BuOK (3.80 mL of a 1.0 M solution in THF) wasadded to a stirred solution of acetone oxime (285 mg, 3.82 mmol) in THF(5 mL) at room temperature. The reaction mixture was further dilutedwith THF (20 mL) and after 30 minutes cooled to 0° C. A solution of2-(2-chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl ester(15) (600 mg, 1.86 mmol) in THF (5 mL) was added. The reaction mixturewas slowly warmed to room temperature. After 90 minutes, the reactionmixture was quenched with saturated NH₄Cl and diluted with EtOAc. Theorganic layer was washed with saturated NH₄Cl and brine, dried (MgSO₄)and concentrated. The residue (16) was diluted with MeOH (10 mL) and asolution of 2 M HCl in diethyl ether (10 mL) was added. After 16 hours,the reaction mixture was diluted with EtOAc, washed with water,saturated NaHCO₃ and water. The organic layer was dried (MgSO₄) andconcentrated. Purification by flash column chromatography using theBiotage system (1.5% MeOH in CH₂Cl₂) provided 399 mg (64%) of thedesired product (17).

Step C: Preparation of3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylicacid methyl ester (18): Compound 18 was prepared according to Step G ofExample 1 using compound 17 as the starting material.

Step D: Preparation of3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluoro-benzo[d]isoxazole-5-carboxylicacid (19): Compound 19 was prepared according to Step H of Example 1using3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylicacid methyl ester (18) as the starting material to provide 188 mg (98%yield) of compound 19. MS APCI (−) m/z 398, 400 (M+, Br, Cl pattern)detected: ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.49 (s, 1H), 7.73(m, 1H), 7.41 (dd, 1H), 6.92 (t, 1H), 6.76 (s, 2H): ¹⁹F NMR (376 MHz,DMSO-d₆)-141.48 (s, 1F).

Example 8

Synthesis of 3-amino-6-(4-bromo-2-chloro-phenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylic acid (2-hydroxyethoxy)-amide (21).

The reaction scheme for the synthesis of compound 21, as shown in FIG.6, was accomplished according to Steps A and B of Example 3 using3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylicacid (19) as the starting material to provide 16 mg (23% yield for twosteps) of compound 21. MS APCI (−) m/z 457, 459 (M+, Br, Cl pattern)detected: ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 8.59 (s, 1H), 7.94(s, 1H), 7.69 (s, 1H), 7.36 (d, 1H), 6.75 (dd, 1H), 6.71 (s, 2H), 4.73(s, 1H), 3.87 (s, 2H), 3.59 (s, 2H): ¹⁹F NMR (376 MHz, DMSO-d₆)-140.64(s, 1F).

Example 9

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (30)

The reaction scheme for the synthesis of compound 30 is shown in FIG. 7

Step A: Preparation of 4,6-dichloronicotinic acid ethyl ester (22):POCl₃ (100 mL, 1092 mmol) was added to 4,6-dihydroxynicotinic acid ethylester (J. Heterocyclic Chem. 1983, 20, 1363) (20.0 g, 109 mmol). Theresulting suspension was cooled to 0° C. and triethylamine (15.2 mL, 109mmol) was added dropwise at such a rate as to maintain the internalreaction mixture temperature below 25° C. Upon completion of addition,the reaction mixture was warmed to room temperature and then to 80° C.After 4 hours, the reaction mixture was cooled to room temperature andstirred for 16 hours. The reaction mixture was carefully poured onto 2 Lcrushed ice. The mixture was extracted with EtOAc and diethyl ether. Thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated. The dark brown liquid was purified by passing through aplug of silica gel (CH₂Cl₂) to give the desired product (22) as a lowmelting yellow solid (18.7 g, 78%).

Step B: Preparation of 4,6-dichloronicotinic acid (23): Sodium hydroxide(40 mL, 6.25 M solution) was added to a stirred solution of4,6-dichloronicotinic acid ethyl ester (22) (25.95 g, 118 mmol) in 4:1:1THF:MeOH:water (600 mL). After 30 minutes, the reaction mixture wasacidified to pH 2 with concentrated HCl, diluted with 1:1 EtOAc:Et₂O andwashed with water and brine. The organic layer was dried (Na₂SO₄) andconcentrated. The resulting off-white solid was twice concentrated fromtoluene to give the desired product (23) as a white solid (21.73 g,96%).

Step C: Preparation of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinicacid hydrochloride salt (24): LiHMDS (261 mL of a 1M solution inhexanes) was added dropwise over 30 minutes to a solution of4-bromo-2-chlorophenylamine (35.0 g, 172 mmol) in THF (80 mL) at −78° C.After 1 hour, 4,6-dichloronicotinic acid (23) (15.7 g, 81.7 mmol) wasadded dropwise over 30 minutes. The reaction mixture was slowly warmedto room temperature and stirred 16 hours. The reaction mixture wasquenched with water, diluted with EtOAc and acidified with 1N HCl. Theresulting precipitate was isolated by filtration and washed with EtOAc.The solids were twice concentrated from toluene, triturated with CH₂Cl₂and collected by filtration. The solids were further concentrated fromtoluene (3×) followed by drying in vacuo to give the desired product(24) containing a small amount of water (36.0 g).

Step D. Preparation of4-(4-Bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid (25):N-Chlorosuccinimide was (13.0 g, 99.0 mmol) added to a suspension of4-(4-bromo-2-chloro-phenylamino)-6-chloro-nicotinic acid (24) (32.54 g,89.9 mmol) in DMF (500 mL). The suspension was allowed to stir at roomtemperature overnight. The reaction mixture was diluted with saturatedsodium bisulfite (200 mL) and water (1L) resulting in formation of athick white precipitate which was isolated by filtration and washed withwater. The solids were dissolved into THF. Two volumes of diethyl etherwere added and the organic solution washed with brine, dried over NaSO₄,filtered, and concentrated in vacuo to provide an orange solid. Thesolid was triturated with diethyl ether to provide the desired productas an off-white solid (25) (13.34 g, 37%). MS (APCI−) m/z 393, 395, 397(M−; Cl, Br pattern) detected.

Step E. Preparation of4-(4-Bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid methylester (26): Trimethylsilyldiazomethane (2.0 M solution in hexanes, 37mL, 74 mmol) was added slowly to a suspension of4-(4-bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid (25) (14.67g, 37 mmol). After the addition was complete the resulting slurry wasdiluted with hexanes (600 mL) and the solids isolated by filtrationwashing with hexanes. The desired product was isolated as an off-whitesolid (10.06 g). The hexanes washes were concentrated and the solidspassed through a plug of silica gel eluting with dichloromethane.Concentration of the product-containing fractions provided an additional3.83 g desired product (26) for a total of 13.89 g (91%). MS (APCI+) m/z409, 411, 413 (M+; Cl, Br pattern) detected.

Step F. Preparation of6-Azido-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid methylester (27): Sodium azide (4.4 g, 68 mmol) was added to a suspension of4-(4-bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid methylester (26) (13.89 g, 33.8 mmol) in DMF (200 mL) and the mixture allowedto stir at room temperature overnight. The solution was diluted withwater (600 mL) and the resulting white precipitate was collected byfiltration and washed with water. The solids were dissolved into THF.Two volumes of diethyl ether were added and the organic solution washedwith brine, dried over NaSO₄, filtered, and concentrated in vacuo to thedesired product (27) as a light yellow solid (12.94 g, 92%).

Step G. Preparation of6-Amino-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid methylester (28): Zinc powder (10 g, 155 mmol) was added portionwise to asuspension of6-azido-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid methylester (27) (12.94 g, 31 mmol) in 3:1 dichloromethane/acetic acid (300mL). After fifteen minutes the reaction mixture was poured into 700 mLethyl acetate, washed with water, saturated sodium bicarbonate andbrine. The organic solution was dried over NaSO₄, filtered, andconcentrated in vacuo to provide the desired product (28) as anoff-white solid (11.85 g, 98%). MS (APCI+) m/z 390, 392, 394 (M+; Cl, Brpattern) detected.

Step H. Preparation of7-(4-Bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (29): Chloroacetaldehyde (50% aqueous solution, 0.70mL, 5.7 mmol) was added to a suspension of6-amino-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid methylester (28) in DMF (7 mL) contained in a sealed tube. The reactionmixture was heated at 80° C. for four hours and then allowed to cool toroom temperature and stir overnight. The dark brown solution was dilutedwith water (70 mL) the resulting light brown precipitate was collectedby filtration and washed with water. The solids were dissolved into THF.Two volumes of ethyl acetate were added and the organic solution washedwith brine, dried over NaSO₄, filtered, and concentrated in vacuo toprovide a brown solid. The aqueous filtrate was extracted with ethylacetate and the organic extracts were dried over NaSO₄, filtered, andconcentrated in vacuo. This material was combined with the previouslyisolated brown solid and the combined material subjected to columnchromatography (dichloromethane, followed by 20:1dichloromethane/methanol). The desired product (29) was isolated as alight yellow solid (0.752 g, 64%). MS (APCI+) m/z 414, 416, 418 (M+; Cl,Br pattern) detected.

Step I. Preparation of7-(4-Bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylicacid (30): Sodium hydroxide (1.0 M aqueous solution, 14.6 mL, 14.6 mmol)was added to a solution of7-(4-bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (29) in methanol (30 mL) and the solution allowed tostir at room temperature overnight. Methanol was removed by rotaryevaporation and the solution diluted with water and acidified to pH 2 byaddition of 1.0 M HCl. The aqueous suspension was extracted with 4:1ethyl acetate/THF. The organic extracts were washed with brine, driedover NaSO₄, filtered, and concentrated in vacuo to provide the desiredproduct as a light orange solid (30). MS (APCI+) m/z 400, 402, 404 (M+:Cl, Br pattern) detected: ¹H NMR (400 MHz, methanol-d₄) δ 9.01 (s, 1H),7.83 (s, 1H), 7.51 (s, 2H), 7.25 (d, 1H), 6.60 (d, 1H).

Example 10

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (31)

FIG. 8 shows the reaction scheme for the synthesis of compound 31, whichwas prepared according to the method of Example 2, using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (30) as the starting material to provide 4.1 g (53% yield) ofcompound 31. MS (APCI−) m/z 467, 469, 471 (M−: Cl, Br pattern) detected:¹H NMR (400 MHz, methanol-d₄) δ 8.76 (s, 1H), 7.95 (d, 1H), 7.64 (d,1H), 7.56 (d, 1H), 7.26 (dd, 1H), 6.56 (d, 1H), 3.57 (d, 2H), 1.10 (m,1H), 0.54 (m, 2H), 0.24 (m, 2H).

The following compounds were synthesized in a similar manner as shown inFIGS. 7, 8, and 9 using the appropriate aniline in Step C of Example 9.

7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

MS ESI (+) m/z 453, 455, 457 (M+, Cl, Br pattern) detected. ¹H NMR (400MHz, CD₃OD) δ 8.70 (s, 1H), 7.95 (s, 1H), 7.67 (s, 1H), 7.34 (m, 1H),7.20 (m, 1H), 6.79 (m, 1H), 3.49 (m, 2H), 1.08 (m, 1H), 0.55 (m, 2H),0.26 (m, 2H). ¹⁹F NMR (376 MHz, CD₃OD)

Synthesis of8-chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxy-amide

MS ESI (+) m/z 375, 377 (M+, Cl pattern) detected. ¹H NMR (400 MHz,CD₃OD) δ 8.70 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 7.09 (m, 1H), 7.00(m, 1H), 6.95 (m, 1H), 6.77 (m, 1H), 3.47 (d, 2H), 1.05 (m, 1H), 0.51(m, 2H), 0.22 (m, 2H). ¹⁹F NMR (376 MHz, CD₃OD) 6-132.1.

Synthesis of7-(4-bromo-2-fluor-phenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)-amide

MS ESI (+) m/z 443, 445, 447 (M+, Cl, Br pattern) detected. ¹H NMR (400MHz, CD₃OD) δ 8.74 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.32 (m, 1H),7.16 (m, 1H), 6.68 (m, 1H), 3.84 (t, 2H), 3.66 (t, 2H). ¹⁹F NMR (376MHz, CD₃OD) 6-128.9.

8-Chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)-amide

MS ESI (+) m/z 365, 367 (M+, Cl pattern) detected. ¹H NMR (400 MHz,CD₃OD) δ 8.73 (s, 1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.10 (m, 1H), 7.00(m, 1H), 6.94 (m, 1H), 6.77 (m, 1H), 3.78 (t, 2H), 3.62 (t, 2H). ¹⁹F NMR(376 MHz, CD₃OD) 6-131.9.

Synthesis of8-chloro-7-(2,4-dichlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide

MS APCI (−) m/z 413, 415, 417 (M-, Cl pattern) detected: ¹H NMR (400MHz, CD₃OD) δ 8.78 (s, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.10 (dd, 1H),6.61 (d, 1H), 4.0 (m, 2H), 3.72 (m, 2H).

7-(4-Bromo-2-fluorophenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylicacid

MS ESI (+) m/z 384, 386, 388 (M+, Cl, Br pattern) detected. ¹H NMR (400MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 7.53 (m, 1H),7.23 (m, 1H), 6.75 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) 6-127.9.

8-Chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid

MS ESI (+) m/z 306, 308 (M+, Cl pattern) detected. ¹H NMR (400 MHz,DMSO-d₆) δ 9.30 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.22 (dd, 1H), 7.06(dd, 1H), 6.98 (m, 1H), 6.84 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆)δ-130.5.

8-Chloro-7-(4-chloro-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid

MS ESI (+) m/z 340, 342 (M+, Cl pattern) detected. ¹H NMR (400 MHz,DMSO-d₆) δ 9.29 (s, 1H), 8.10 (s, 1H). 7.68 (s, 1H), 7.43 (m, 1H), 7.12(m, 1H), 6.83 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) 6-127.8.

8-Chloro-7-(4-chloro-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

MS ESI (+) m/z 409, 411 (M+, Cl pattern) detected. ¹H NMR (400 MHz,CD₃OD) δ 9.97 (br s, 1H), 8.82 (s, 1H). 7.73 (s, 1H), 7.71 (s, 1H), 7.18(m, 1H), 6.97 (m, 1H), 6.56 (m, 1H), 6.47 (br s, 1H), 3.60 (m, 2H), 1.00(m, 1H), 0.56 (m, 2H), 0.24 (m, 2H). ⁹F NMR (376 MHz, CD₃OD) δ-128.7.

Example 11

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)-amide (33a)

The reaction scheme for the synthesis of compound 33a is shown in FIG.9, which was prepared according to Steps A and B of Example 3 using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (30) to provide 44 mg (40% yield for two steps) of the desiredproduct. MS (APCI+) m/z 459, 461, 463 (M⁺: Cl, Br pattern) detected: ¹HNMR (400 MHz, methanol-d₄) δ 8.90 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H),7.69 (s, 1H), 7.45, (d, 1H), 7.06 (m, 1H), 3.86 (br s, 2H), 3.72 (br s,2H).

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (36)

The reaction scheme for the synthesis of compound 36 is shown in FIG.10.

Step A:7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (34): Preparation was accomplished by modification ofthe procedure of Katritzky et al. (J. Org. Chem., 2003, 68, 4935-4937:J. Org. Chem., 1990, 55, 3209-3213). Bis(benzotriazazole) adduct (formedwith 1-methylpiperazine) (106 mg, 0.230 mmol) was added to a suspensionof 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid methylester (28) (30 mg, 0.076 mmol) in dichloroethylene (1 mL) followed bythe addition of ZnBr₂ (52 mg, 0.230 mmol). The reaction mixture wasstirred at reflux for 10 hours and then at room temperature for 16hours. The reaction mixture was diluted with CH₂Cl₂ and filtered. Thefiltrate was washed with water. The aqueous layer was extracted withCH₂Cl₂. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated. Purification by flash column chromatographyusing the Biotage system (60:1 CH₂Cl₂:MeOH) provided the desired product(34) as a yellow solid (31 mg, 79%).

Step B:7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (36): Sodium hydroxide (59 μL, 1M solution)was added to a suspension of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (34) in MeOH (1 mL). After stirring 18 hours, thereaction mixture was concentrated to dryness. The residue (35) wasdiluted with toluene and concentrated (repeated), and 31 mg of therecovered yellow residue (35) was carried forward without purification.The residue (35) was suspended in CH₂Cl₂ (1 mL), cooled to 0 C andoxalyl chloride (150 μL of a 2 M solution in CH₂Cl₂) was added. One dropof DMF was added and the reaction mixture warmed to room temperature.After 10 minutes, concentration of the mixture was followed byconcentrating from toluene twice and then drying in vacuo. The resultingyellow solid was suspended in CH₂Cl₂ (1 mL), cooled to 0 C andcyclopropylmethylhydroxylamine (16 mg, 0.180 mmol) was added. After thereaction mixture was warmed to room temperature and stirred for 16hours, it was diluted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried (Na₂SO₄) and concentrated.Purification by flash column chromatography using the Biotage system(15:1 CH₂Cl₂:MeOH) provided the desired product (36) as a pale yellowsolid (12 mg, 37%).

MS ESI (+) m/z 567, 569, 571 (M+, Cl, Br pattern) detected: ¹H NMR (400MHz, CD₃OD) δ 8.35 (s, 1H), 7.55 (d, 1H), 7.38 (s, 1H), 7.25 (dd, 1H),6.54 (d, 1H), 3.59 (d, 2H), 3.17 (t, 4H), 2.74 (m, 4H), 2.43 (s, 3H),1.09 (m, 1H), 0.54 (m, 2H), 0.24 (m, 2H).

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-yl-imidazo[1,2-a]-pyridine-6-carboxylicacid cyclopropylmethoxyamide (37)

The reaction scheme for the synthesis of compound 37 is shown in FIG.10. Compound 37 was prepared according to Steps A and B of Example 12using 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acidmethyl ester (28) and the bis(benzotriazazole) adduct (formed withmorpholine) to provide 2 mg (8% yield for two steps) of the desiredproduct (37). MS ESI (+) m/z 554, 556, 558 (M+, Cl, Br pattern)detected: ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.55 (d, 1H), 7.38 (s,1H), 7.26 (dd, 1H), 6.54 (d, 1H), 3.91 (t, 4H), 3.59 (d, 2H), 3.11 (t,4H), 1.08 (m, 1H), 0.54 (m, 2H), 0.24 (m, 2H).

Example 14

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-dimethylaminoimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (38)

The reaction scheme for the synthesis of compound 38 is shown in FIG.10. Compound 38 was prepared according to Steps A and B of Example 12using 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acidmethyl ester (28) and the bis(benzotriazazole) adduct (formed withdimethylamine) providing 16 mg (37% yield for two steps) of the desiredproduct (38). MS ESI (+) m/z 512, 514, 516 (M+, Cl, Br pattern)detected: ¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.54 (d, 1H), 7.30 (s,1H), 7.24 (dd, 1H), 6.52 (d, 1H), 3.59 (d, 2H), 2.86 (s, 6H), 1.07 (m,1H), 0.53 (m, 2H), 0.23 (m, 2H).

Example 15

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-piperidin-1-ylmethylimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (39)

The reaction scheme for the synthesis of compound 39 is shown in FIG.11. Compound 39 was prepared by a modification of the procedure ofKercher et al. (manuscript in preparation). Piperidine (4 μL, 0.043mmol) and 37% aqueous formaldehyde (5 μL, 0.065 mmol) were dissolved in6:1 MeCN:water (0.5 ml), and stirred 30 minutes.7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) (10 mg, 0.022 mmol) was added followedby scandium triflate (1 mg, 0.002 mmol). After stirring 16 hours,additional scandium triflate (1 mg), piperidine (3.8 μL) and aqueousformaldehyde (3.8 μL) were added. After about 60 hours, the reactionmixture was diluted with EtOAc and washed with water, 10% K₂CO₃, andbrine. The organic layer was dried (Na₂SO₄) and concentrated.Purification by flash column chromatography using the Biotage system(40:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH to 9:1 CH₂Cl₂:MeOH) provided thedesired product (39) as a white solid (6 mg, 50%). MS APCI (+) m/z 556,558, 560 (M+, Cl, Br pattern) detected: ¹H NMR (400 MHz, CD₃OD) δ 8.83(s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.27 (dd, 1H), 6.56 (d, 1H), 3.91(m, 4H), 3.70 (m, 2H), 2.51 (broad s, 4H), 1.60 (broad s, 4H), 1.50(broad s, 2H).

The following compounds were synthesized in a similar manner as shown inFIG. 11.

7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-ylmethyl-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxy-amide

The reaction scheme for the synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-ylmethyl-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxy-amide is similar to that shown in FIG. 11 using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) and morpholine to provide the desiredproduct. MS APCI (+) m/z 568, 570, 572 (M+, Cl, Br pattern) detected; ¹HNMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.04 (s, 1H), 7.56 (d, 1H), 7.21(dd, 1H), 6.68 (d, 1H), 4.51 (s, 2H), 4.00 (m, 4H), 3.78 (d, 2H), 1.68(m, 1H), 0.56 (m, 2H), 0.26 (m, 2H).

7-(4-Bromo-2-chlor-phenylamino)-8-chloro-3-dimethylaminomethyl-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

The reaction scheme for the synthesis of7-(4-bromo-2-chlor-phenylamino)-8-chloro-3-dimethylaminomethyl-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide was similar to that shown in FIG. 11, using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) and dimethylamine to provide thedesired product. MS APCI (+) m/z 528, 530, 532 (M+, Cl, Br pattern)detected; ¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 7.50 (d, 1H), 7.44 (s,1H), 7.20 (dd, 1H), 6.55 (d, 1H), 3.80 (s, 2H), 3.74 (d, 2H), 2.04 (s,6H), 1.18 (m, 1H), 0.51 (m, 2H), 0.27 (m, 2H).

4-[7-(4-Bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoylimidazo[1,2-a]pyridin-3-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

The reaction scheme for the synthesis of4-[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoylimidazo[1,2-a]pyridin-3-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester was similar to that shown in FIG. 11, using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) and piperazine-1-carboxylic acidtert-butyl ester to provide the desired product. MS APCI (+) m/z 669,671, 673 (M+, Cl, Br pattern) detected;

¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.00 (s, 1H), 7.56 (d, 1H), 7.27(dd, 1H), 6.67 (d, 1H), 4.54 (s, 2H), 3.76 (d, 4H), 3.27 (m, 4H), 1.50(s, 9H), 1.12 (m, 1H), 0.55 (m, 2H), 0.28

7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

The reaction scheme for the synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide was similar to that shown in FIG. 11 using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) and 1-methylpiperazine to provide thedesired product. MS APCI (+) m/z 581, 583, 585 (M+, Cl, Br pattern)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.57 (s, 1H), 7.56 (d,1H), 7.22 (dd, 1H), 6.47 (d, 1H), 3.83 (s, 2H), 3.60 (d, 2H), 2.47 (m,8H), 2.31 (s, 3H), 1.02 (m, 1H), 0.56 (m, 2H), 0.26 (m, 2H).

7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide was prepared using7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)amide (33a) and 1-methyl-piperazine to provide thedesired product. MS APCI (+) m/z 581, 583, 585 (M+, Cl, Br pattern)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.57 (s, 1H), 7.56 (d,1H), 7.22 (dd, 1H), 6.47 (d, 1H), 3.83 (s, 2H), 3.60 (d, 2H), 2.47 (m,8H), 2.31 (s, 3H), 1.02 (m, 1H), 0.56 (m, 2H), 0.26 (m, 2H).

Example 16

Synthesis of7-(4-bromo-2-chlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acidcyclopropylmethoxyamide (44a)

The reaction scheme for the synthesis of compound 44a is shown in FIG.12.

Step A: Preparation of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinicacid tert-butyl ester (40): 2-tert-Butyl-1,3-diisopropylisourea (8.04 g,40.1 mmol) was added to a mixture of4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid hydrochloridesalt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After stirring for 2hours at room temperature and 30 minutes at reflux, the reaction mixturewas cooled to room temperature and diluted with EtOAc. The organic layerwas washed with 10% K₂CO₃ and brine, dried (Na₂SO₄) and concentrated.The resulting residue was dissolved in CH₂Cl₂ and filtered. The filtratewas concentrated and purified by flash column chromatography using theBiotage system (CH₂Cl₂) to give the desired product (40) (3.28 g, 78%).

Step B: Preparation of 6-azido-4-(4-bromo-2-chlorophenyl-amino)nicotinicacid tert-butyl ester (41): Sodium azide (1.51 g, 23.2 mmol) was addedto a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acidtert-butyl ester (40) (3.23 g, 7.73 mmol) in DMF (60 mL). The reactionmixture was heated to 80° C. and stirred for 16 hours. After cooling toroom temperature, the reaction was diluted with EtOAc and washed withwater, saturated NaHCO₃ and brine. The organic layer was dried (Na₂SO₄)and concentrated. Purification by flash column chromatography using theBiotage system (CH₂Cl₂) (repeated) provided the desired product (41)(1.41 g, 43%).

Step C: Preparation of 6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinicacid tert-butyl ester (42): Compound 42 was prepared as described inStep G of Example 9 using6-azido-4-(4-bromo-2-chlorophenylamino)nicotinic acid tert-butyl ester(41).

Step D: Preparation of7-(4-bromo-2-chlorophenylamino)imidazo[1,2-a]pyridine-6-carboxylic acid(43): Chloroacetaldehyde (12 μL, 0.188 mmol) was added to a mixture of6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid tert-butyl ester(42) (50 mg, 0.125 mmol) in EtOH (630 μL). After stirring the reactionmixture at 80° C. for 5 hours, an additional 12 μL of chloroacetaldehydewere added and heating was continued for 10 hours. The reaction mixturewas cooled to room temperature and diluted with EtOAc to give a cloudysemi-solution. The organic layer was washed with water, saturated NaHCO₃and brine. The organic layer contains a precipitate, which was collectedby filtration to give the desired product (43) (15 mg, 33%).

Step E: Preparation of7-(4-bromo-2-chlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acidcyclopropylmethoxyamide (44a): Oxalyl chloride (102 μL of a 2.0 Msolution in CH₂Cl₂) was added to a stirred suspension of7-(4-bromo-2-chlorophenylamino)imidazo[1,2-a]pyridine-6-carboxylic acid(43) (15 mg, 0.041 mmol) in CH₂Cl₂ (1 mL) at 0° C. One drop of DMF wasadded. The reaction mixture was warmed to room temperature, stirred for25 minutes, and then concentrated. The residue was twice concentratedfrom toluene and dried in vacuo. The residue was suspended in CH₂Cl₂ (1mL), cooled to 0 C and cyclopropylmethylhydroxylamine (36 mg, 0.409mmol) was added. The reaction mixture was warmed to room temperature,stirred for 2 hours and diluted with EtOAc. The organic layer was washedwith saturated NaHCO₃ and brine, dried (Na₂SO₄) and concentrated.Purification by flash column chromatography using the Biotage system(40:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) provided the desired product(44a) as a tan solid (6 mg, 31%). MS APCI (−) m/z 433, 435 (M-, Cl, Brpattern) detected: ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.69 (m, 1H),7.67 (d, 1H), 7.52-7.44 (m, 3H), 7.08 (s, 1H), 3.83 (d, 2H), 0.90 (m,1H), 0.62 (m, 2H), 0.35 (m, 2H).

The following compounds were synthesized in a similar manner as shown inFIG. 12 using the appropriate aniline in Step C of Example 9.

7-(4-Bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid

MS ESI (+) m/z 350, 352 (M+, Br pattern) detected. (400 MHz, DMSO-d₆) δ9.13 (s, 1H), 7.94 (d, 1H). 7.70 (dd, 1H), 7.67 (d, 1H), 7.59 (t, 1H),7.47 (m, 1H), 6.84 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) 6-128.9.

7-(4-Bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acidcyclopropylmethoxyamide

MS ESI (+) m/z 419, 421 (M+, Br pattern) detected. ¹H NMR (400 MHz,DMSO-d₆) δ 11.91 (br s, 1H), 8.79 (s, 1H), 8.72 (br s, 1H), 7.81 (s,2H), 7.64 (m, 1H), 7.50 (m, 1H), 7.45 (m, 1H), 7.39 (m, 1H), 6.90 (s,1H), 3.74 (d, 2H), 1.14 (m, 1H), 0.55 (m, 2H), 0.29 (m, 2H). ¹⁹F NMR(376 MHz, DMSO-d₆) 6-124.3.

7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid(2-hydroxyethoxy)-amide

MS ESI (+) m/z 409, 411 (M+, Br pattern) detected. ¹H NMR (400 MHz,DMSO-d₆) δ 12.02 (br s, 1H), 8.83 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H),7.51 (m, 1H), 7.45 (m, 1H), 7.39 (m, 1H), 6.91 (s, 1H), 4.79 (br s, 1H),3.94 (t, 2H), 3.64 (t, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) 6-124.4.

Example 17

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (47a)

The reaction scheme for the synthesis of compound 47a is shown in FIG.13.

Step A: Preparation of6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acidtert-butyl ester (45):1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (889 mg, 2.508 mmol) was added to a mixture of6-amino-4-(4-bromo-2-chlorophenylamino)nicotinic acid tert-butyl ester(42) (1.00 g, 2.51 mmol) in 1:1 MeOH:water (25 mL). After about 2 hours,the reaction mixture was diluted with EtOAc and water. The layers wereseparated and the organic layer washed with 0.5 N HCl and brine. Theaqueous washes were back extracted with EtOAc. The combined organicextracts were dried (Na₂SO₄) and concentrated. Purification by flashcolumn chromatography using the Biotage system (20:1 hexanes:EtOAc to15:1 hexanes:EtOAc) provided the desired product (45) as a yellow solid(75 mg, 7%).

Step B: Preparation of7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid (46): Chloroacetaldehyde (23 μL, 0.360 mmol) was added to a mixtureof 6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acidtert-butyl ester (45) (75 mg, 0.180 mmol) in EtOH (1 mL). After stirringthe reaction mixture at 70° C. for 10 hours, an additional 10 μLchloro-acetaldehyde was added and heating was continued for 33 hours.The reaction mixture was cooled to room temperature and desired product(46) was collected by filtration. The filtrate was diluted with EtOAcand washed with water, saturated NaHCO₃ and brine. The organic layer wasdried (Na₂SO₄) and concentrated to give additional product (46) (51 mg,74% combined recovery).

Step C: Preparation of7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (47a): Compound 47 was prepared asdescribed in Step E of Example 16 using7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid (46) to give 15 mg (24%) of the desired product (47a) as a whitesolid. MS APCI (+) m/z 453, 455, 457 (M+, Cl, Br pattern) detected: ¹HNMR (400 MHz, CD₃OD) δ 8.66 (s, 1H), 7.93 (m, 1H), 7.61 (s, 1H), 7.56(d, 1H), 7.32 (dd, 1H), 6.73 (q, 1H) 3.70 (d, 2H), 1.14 (m, 1H), 0.56(m, 2H), 0.26 (m, 2H): ¹⁹F (400 MHz, CD₃OD)-139.4 (s, 1F).

The following compounds were synthesized in a similar manner as shown inFIG. 13.

7-(4-Bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxy-ethoxy)amide

MS APCI (+) m/z 443, 445, 447 (M+, Cl, Br pattern) detected; ¹H NMR (400MHz, CD₃OD) δ 8.69 (s, 1H), 7.89 (m, 1H), 7.59 (s, 1H), 7.55 (d, 1H),7.31 (dd, 1H), 6.72 (q, 1H), 4.01 (t, 2H), 3.76 (t, 2H); ¹⁹F (400 MHz,CD₃OD)-139.7 (s, 1F).

7-(4-Bromo-2-fluorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid

MS ESI (+) m/z 368, 370 (M+, Br pattern) detected.

7-(4-Bromo-2-fluorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide

MS ESI (+) m/z 437, 439 (M+, Br pattern) detected. ¹H NMR (400 MHz,CD₃OD) δ 9.55 (br s, 1H), 8.57 (s, 1H). 7.68 (s, 2H), 7.65 (s, 1H), 7.28(m, 1H), 7.14 (m, 1H), 6.78 (br s, 1H), 6.63 (m, 1H), 3.72 (m, 2H), 1.07(m, 1H), 0.59 (m, 2H), 0.28 (m, 2H).

¹⁹F NMR (376 MHz, CD₃OD) δ−128.9, −138.1.

Example 18

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]-triazolo-[4,3-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (53a)

The reaction scheme for the synthesis of compound 53a is shown in FIG.14.

Step A: Preparation of4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid ethylester (49): 4-(4-Bromo-2-chlorophenylamino)-5,6-dichloronicotinic acidethyl ester (48) was prepared by standard methods from4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid. Hydrazinemonohydrate (0.59 mL, 12.16 mmol) was added to a solution of4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl ester(48) (1.72 g, 4.05 mmol) in N,N-dimethylacetamide (20 mL). Afterstirring at 90° C. for 1 hour, the reaction mixture was cooled to roomtemperature and diluted with EtOAc. The organic layer was washed withwater and brine, dried (Na₂SO₄) and concentrated. Purification by flashcolumn chromatography using the Biotage system (20:1 CH₂Cl₂:EtOAc)provided the desired product (49) (307 mg, 18%).

Step B: Preparation of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid ethyl ester (51a): Acetic anhydride (22 μL, 0.238 mmol) was addedto a solution of4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid ethylester (49) (0.100 g, 0.238 mmol) and triethylamine (66 μL, 0.476 mmol)in CH₂Cl₂ (2.5 mL) at 0° C., and then the solution was warmed to roomtemperature to provide compound 50a (not isolated). After 10 minutes,POCl₃ (87 μL, 0.952 mmol) was added dropwise and the reaction mixturewas warmed to room temperature. After 16 hours, the reaction mixture washeated to reflux and stirred for 3 days. The reaction mixture was cooledto room temperature and concentrated. The residue was diluted with EtOAcand saturated NaHCO₃ was added and the mixture stirred for 20 minutes.The layers were separated and the organic layer was washed with brine.The aqueous washings were back extracted with EtOAc. The combinedorganic extracts were dried (Na₂SO₄) and concentrated. Purification byflash column chromatography using the Biotage system (9:1 CH ₂Cl₂:EtOAc)provided compound 51a (80 mg, 75%).

Step C: Preparation of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (52a): Sodium hydroxide (715 μL of a 1M solution) was added to asolution of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid ethyl ester (51a) (79 mg, 179 mmol) in 3:1 THF:water (4.5 mL).After 16 hours, the reaction mixture was poured into a separatoryfunnel, diluted with brine and acidified with 1N HCl to about pH 2. Theaqueous layer was extracted with 1:1 EtOAc:THF. The combined organicextracts were dried (Na₂SO₄) and concentrated and the residue (52a) wascarried forward without further purification.

Step D: Preparation of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (53a): Compound 53a was prepared asdescribed in Example 2 using7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (52a) to give 2 mg (5%) of the desired product. MS APCI (−) m/z482, 484, 486 (M-, Cl, Br pattern) detected.

Example 19

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)-amide (54a)

The reaction scheme for the synthesis of compound 54a is shown in FIG.14. Compound 54a was prepared as described herein starting with7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (52a) to give 1 mg (2% for the two steps) desired product (54a). MSAPCI (−) m/z 472, 474, 476 (M-, Cl, Br pattern) detected.

Synthesis of3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (53b)

The reaction scheme for the synthesis of compound 53b is shown in FIG.14.

Step A: Preparation of3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid methyl ester (51b): Phenylacetyl chloride (152 μL, 1.148 mmol) wasadded to a solution of4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acidmethyl ester (49) (0.233 g, 0.574 mmol) and triethylamine (160 μL, 1.148mmol) in CH₂Cl₂ (5.7 mL) at 0° C. After warming to room temperature, anadditional 75 μL phenylacetyl chloride was added. After 6 hours, thereaction mixture was concentrated and diluted with EtOAc. The organiclayer was washed with water and brine, dried (Na₂SO₄) and concentrated.The residue (50b) was diluted with dichloroethylene (2 mL) and POCl₃(465 μL, 5.082 mmol) was added. After stirring at reflux for 12 hours,the reaction mixture was cooled to room temperature and concentrated.The residue was diluted with EtOAc and saturated NaHCO₃ was added andthe mixture stirred for 20 minutes. The resulting solid was collected byfiltrate to give the desired product (5 lb) (97 mg, 30%).

Step B: Preparation of3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (53b): Compound 53b was prepared asdescribed in Step C of Example 18 and Example 2 using3-benzyl-7-(4-bromo-2-chloro-phenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid methyl ester (5 lb) as the starting material to give 5 mg (4% forthe two steps) of the desired product (53b). MS APCI (−) m/z 558, 560,562 (M-, Cl, Br pattern) detected:

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.30 (m, 6H), 6.50 (d, 1H), 4.53(s, 2H), 3.49 (m, 2H), 0.94 (m, 1H), 0.51 (m, 2H), 0.19 (m, 2H).

Example 21

Synthesis of6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylicacid (56)

The synthesis of compound 56 is shown in FIG. 15.

Step A: Preparation of6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylicacid methyl ester (55): Sodium azide (128 mg, 1.95 mmol) was added to amixture of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acidmethyl ester (6) (601 mg, 1.59 mmol) in 3:1 acetone:water (16 ml) andheated to reflux. After 16 hours, the reaction mixture was cooled toroom temperature, and diluted with EtOAc and water. The organic layerwas washed with water, dried (MgSO₄) and concentrated. The resultingresidue was diluted with water (8 mL) and heated to reflux. After 5hours, the mixture was cooled to room temperature and diluted withEtOAc. The organic layer was washed with water, dried (MgSO₄) andconcentrated. Purification by flash column chromatography using theBiotage system (20% EtOAc in hexanes) provided the desired product (55)(410 mg, 77%).

Step B: Preparation of6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]-isoxazole-5-carboxylicacid (56): To a solution of6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylicacid methyl ester (55) (100 mg, 0.299 mmol) in 6:1 THF:water (3.5 mL)was added LiOH (0.60 ml of a 1M solution in water). After 1 hour, thereaction was acidified to pH 1 with 1N HCl, diluted with water andextracted with EtOAc. The combined organic extracts were washed withwater, dried (MgSO4) and concentrated to give the desired product (56)(87 mg, 91%). MS APCI (−) m/z 319, 321 (M+, Cl pattern) detected: ¹H NMR(400 MHz, CD₃OD) δ 8.45 (s, 1H), 7.38 (dd, 1H), 7.20 (m, 1H), 6.91 (m,2H), 2.88 (s, 3H): ¹⁹F NMR (376 MHz, CD₃OD)-136.40 (s, 1F).

Example 22

Synthesis of6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylicacid (2-hydroxyethoxy)amide (57a)

Compound 57a was prepared as shown in FIG. 15 using6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylicacid (56) to give 35 mg (44%) desired product. MS APCI (−) m/z 388, 390(M+, Cl pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.73 (s, 1H), 7.36(d, 1H), 7.17 (t, 1H), 6.89 (t, 1H), 6.81 (dd, 1H), 3.72(d, 2H), 2.87(s, 3H), 1.15 (m, 1H), 0.54 (d, 2H), 0.26 (d, 2H); ¹⁹F NMR (376 MHz,CD₃OD)-135.08 (s, 1F).

Example 23

Synthesis of6-(2-Chloro-phenylamino)-7-fluoro-3-methyl-benzo[c]isoxazole-5-carboxylicacid cyclopropylmethoxy-amide (57b)

Compound 57b was prepared as shown in FIG. 15 and described in Example 2using6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylicacid (56) to give 35 mg (44%) desired product. MS APCI (−) m/z 388, 390(M+, Cl pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.73 (s, 1H), 7.36(d, 1H), 7.17 (t, 1H), 6.89 (t, 1H), 6.81 (dd, 1H), 3.72(d, 2H), 2.87(s, 3H), 1.15 (m, 1H), 0.54 (d, 2H), 0.26 (d, 2H); ¹⁹F NMR (376 MHz,CD₃OD)-135.08 (s, 1F).

Synthesis of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methylaminomethyl-imidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxy-amide (63)

The synthesis of compound 63 is shown in FIG. 16.

Step A: Preparation of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formyl-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (58): A suspension of6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloro-nicotinic acid methylester (28) (1.06 g, 2.72 mmol) and 2-chloro-malonaldehyde (587 mg, 5.43mmol) was heated to 80° C. for 45 minutes. The solution was allowed tocool to room temperature, and then washed with saturated aqueous NaHCO₃,and brine. The organic layer was dried over NaSO₄, filtered,concentrated in vacuo, and purified by column chromatography (20:1methylene chloride/methanol) to give the desired product as a darkyellow solid. The solid was triturated with ethyl acetate and isolatedby filtration to provide the desired product as a yellow solid (0.436 g,36%). MS (APCI+) m/z 442, 444, 446 (M+; Cl, Br pattern) detected.

Step B: Preparation of7-(4-bromo-2-chloro-phenylamino)-8-chloro-3-methylaminomethyl-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (59): A suspension of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formylimidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (58) (25 mg, 0.056 mmol), acetic acid (7 μL, 0.11mmol), and methylamine (2.0 M solution in THF, 56 μL, 0.11 mmol) wasstirred for 0.5 hours. Sodium triacetoxyborohydride (36 mg, 0.17 mmol)was added and the solution allowed to stir overnight. The reactionmixture was concentrated to dryness and flashed (dichloromethanefollowed by 10:1 dichloromethane/methanol) to provide the desiredproduct as a yellow solid (12 mg, 46%). MS (APCI+) m/z 455, 457, 459(M+; Cl, Br pattern) detected.

Step C: Preparation of7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (60): Di-tert-butyl dicarbonate (6 mg, 0.029 mmol) andtriethylamine (4 μL, 0.029 mmol) were added to a solution of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyaminomethylimidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (59) (12 mg, 0.026 mmol) in dichloromethane. Thesolution was stirred at room temperature for 0.5 hr after which timeHPLC analysis indicated the reaction had gone to completion. Thesolution was rotovapped to dryness to provide the desired product as ayellow foam (15 mg, quantitative).

MS (APCI+) m/z 557, 559, 561 (M+; Cl, Br pattern) detected.

Step D: Preparation of7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonyl-methylamino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (61): Sodium hydroxide (1.0 M aqueous solution, 0.16 mL, 0.16 mmol)is added to a solution of7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (60) (15 mg, 0.026 mmol) in 4:1 MeOH/water (5 mL).When the reaction was complete, the solution was diluted with water,acidified to pH 3 by addition of 1.0 M aqueous HCl, and extracted withethyl acetate. The organic extracts were dried over NaSO₄, filtered,concentrated in vacuo to provide the desired product as a whitecrystalline solid (12 mg, 84%). MS (APCI−) m/z 541, 543, 545 (M−; Cl, Brpattern) detected.

Step E: Preparation of[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoylimidazo[12-a]pyridin-3-ylmethyl]-methylcarbamicacid tert-butyl ester (62): EDCl (6 mg, 0.033 mmol) and HOBt (5 mg,0.033 mmol) were added to a solution of7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methyl]-8-chloro-imidazo[1,2-a]pyridine-6-carboxylicacid (61) in dimethylacetamide (0.4 mL). The yellow solution was allowedto stir at room temperature for 0.5 hours after which timeO-cyclopropylmethyl-hydroxylamine (6 mg, 0.066 mmol) and triethylamine(6 μL, 0.044 mmol) were added and the solution allowed to stirovernight. The reaction mixture was diluted with ethyl acetate, washedwith water, saturated aqueous ammonium chloride, saturated aqueouspotassium carbonate and brine. The organic phase was dried over NaSO₄,filtered, concentrated in vacuo to provide the desired product as ayellow residue (11.5 mg, 85%). MS (APCI+) m/z 612, 614, 616 (M+; Cl, Brpattern) detected.

Step F: Preparation of7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methylaminomethylimidazo[1,2-a]pyridine-6-carboxylicacid cyclopropylmethoxyamide (63): A solution of[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxy-carbamoyl-imidazo[1,2-a]pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester (62) in 1:1 dichloromethane/trifluoroacetic acidwas stirred for two hours. Solvent was removed under reduced pressureand the residue redissolved into ethyl acetate. The organic solution waswashed with saturated aqueous potassium carbonate and brine. The aqueouswashes were back-extracted with ethyl acetate. The combined organicextracts are dried over NaSO₄, filtered, and concentrated in vacuo toprovide the desired product as a yellow solid (8 mg, 83%). MS (APCI+)m/z 512, 514, 516 (M+; Cl, Br pattern) detected. ¹H NMR (400 MHz,methanol-d₄) δ 8.72 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.25 (d, 1H),6.55 (d, 1H), 4.23 (s, 2H), 3.67 (d, 2H), 2.51 (s, 3H), 1.13 (m, 1H),0.50 (d, 2H), 0.24 (d, 2H).

Example 25

Synthesis of6-(4-bromo-2-chlorophenylamino)-pyrazolo[1,5-a]pyridine-5-carboxylicacid (2-hydroxyethoxy)amide (73a)

Compound 73a, where W═Br, Y═Cl, and X═H, can be prepared as shown inFIG. 17.

Example 26

Synthesis of6-(4-bromo-2-chlorophenylamino)-7-fluoropyrazolo[1,5-a]pyridine-5-carboxylicacid (2-hydroxyethoxy)-amide (73b)

Compound 73b, where W═Br, Y═Cl, and X═F, can be prepared as shown inFIG. 17.

Synthesis of phosphoric acidmono-(2-{[7-(4-bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carbonyl]-aminooxy}-ethyl)ester(74)

The synthesis of compound 74 is shown in FIG. 18.7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid (2-hydroxyethoxy)-amide (33a) (100 mg, 0.234 mmol), tetrazole (23mg, 0.327 mmol) and di-tert-butyl diisopropylphosphoramidite (0.096 mL,0.304 mmol) were dissolved/suspended in 30 mL of anhydrous DMF under anatmosphere of dry N₂. The reaction mixture was stirred for about 3hours, after which time the reaction was cooled to −78° C. andtert-butyl hydrogen peroxide (0.100 mL of 70% solution in water) wasadded. The cooling bath was then taken away and the reaction was slowlywarmed up to room temperature and reacted over night. The reactionmixture was then partitioned between a solution of ethyl ether/ethylacetate (5:1) and saturated aqueous NaHCO₃. The organic layer was savedand successively washed with 10% aqueous sodium sulfite, 3 times withwater and finally with brine. The resulting organic layer was dried overMgSO₄, filtered and concentrated under vacuum. The residue was dissolvedin 3 mL of a solution of TFA/DCM (2:1) under an atmosphere of dry N₂.The reaction was stirred at room temperature for about 2 hours afterwhich time it was concentrated under vacuum and the resulting residuewas stirred in methanol for about 1 hour. The off-white solid wascollected via suction filtration, washed with methanol followed by ethylether and then air-dried to give the desired compound (74).

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound of the Formula (I)

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR⁴R, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R³ is hydrogen,trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an aminoacid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, wherein any of said carbocyclic,heteroaryl or heterocyclic rings are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R′, R″ and R′″ independently are hydrogen, loweralkyl, lower alkenyl, aryl and arylalkyl, and R″″ is lower alkyl, loweralkenyl, aryl and arylalkyl, or any two of R′, R″, R′″ or R″″ togetherwith the atom to which they are attached form a 4 to 10 memberedcarbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl,alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings orheterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R⁴ and R⁵independently are hydrogen or C₁-C₆ alkyl, or R⁴ and R⁵ together withthe atom to which they are attached form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, wherein said alkyl or any of saidcarbocyclic, heteroaryl and heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR′SO₂R″″, —SO₂NR′R″, —C(O)R″″, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″,—NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁶ is trifluoromethyl, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl),—C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) and CR³OR³ whereinany of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl),—C(O)(heteroaryl) and —C(O)(heterocyclyl), CR³OR³ are optionallysubstituted with one or more groups independently selected from —NR³R⁴,—OR³, —R², C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein anyof said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR³; m is 0, 1, 2, 3, 4 or 5; and j is 1 or
 2. 2. The compound of claim1, where R¹ is 2-Cl.
 3. The compound of claim 1, where R⁷ is Me, NH₂ orH.
 4. The compound of claim 1, where R⁸ is Br or Cl.
 5. The compound ofclaim 1, where R⁹ is F.
 6. The compound of claim 1, where W is —C(O)OH,—C(O)NHOCH₂-(cyclopropyl), —C(O)NHO(CH₂)₂OH, or —CONH(SO₂)CH₃.
 7. Thecompound of claim 1, having the formula


8. The compound of claim 1, having the formula


9. The compound of claim 1, having the formula


10. The compound of claim 1, having the formula


11. The compound of claim 1, having the formula


12. The compound of claim 1, having the formula


13. The compound of claim 1, having the formula


14. The compound of claim 1, having the formula


15. The prodrug of claim 1, comprising the compound of Formula Icovalently coupled to an amino acid residue.
 16. The prodrug of claim 1,wherein the amino acid residue is valine.
 17. The prodrug of claim 1,wherein said prodrug is a phosphate ester of the compound of Formula I.18. A composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 19. A method of inhibiting MEKactivity in a mammal comprising administrating to said mammal one ormore compounds of claim 1 in an amount effective to inhibit said MEKactivity.
 20. A method for treatment of a hyperproliferative disorder ina mammal comprising administrating to said mammal one or more compoundsof claim 1 in an amount effective to treat said hyperproliferativedisorder.
 21. A compound of the Formula (II)

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently selected fromhydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, where any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; or R⁷ and R¹¹ together with the atoms to which theyare attached form a 4 to 10 membered saturated, unsaturated, orpartially saturated carbocyclic or heterocyclic ring, wherein any ofsaid saturated, unsaturated, partially saturated carbocyclic orheterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″,—SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R³ is selected from hydrogen, trifluoromethyl, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, phosphate and an amino acid residue,where any of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered saturated,unsaturated, or partially saturated heterocyclic ring, wherein any ofsaid saturated, unsaturated, or partially saturated heterocyclic ringsare optionally substituted with one or more groups independentlyselected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R′, R″ and R′″independently are selected from hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl; R″″ is selected from lower alkyl, lower alkenyl,aryl and arylalkyl, or any two of R′, R″, R′″ or R″″ together with theatom to which they are attached form a 4 to 10 membered saturated,unsaturated, or partially saturated heterocyclic ring, wherein any ofsaid alkyl, alkenyl, aryl, arylalkyl saturated, unsaturated, orpartially saturated heterocyclic rings are optionally substituted withone or more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R⁴ and R⁵ independently represent hydrogen or C₁-C₆alkyl; R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; W is selected from heteroaryl, heterocyclyl,—C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³, C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), C(O)(heteroaryl), —C(O)(heterocyclyl)and —CR³OR³, wherein any of said heteroaryl, heterocyclyl, —C(O)OR³,—C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl) and—C(O)(heterocyclyl), and —CR³OR³ are optionally substituted with one ormore groups independently selected from —NR³R⁴, —OR³, —R², C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein any of said alkyl, alkenyl,and alkynyl portions are optionally substituted with 1 or more groupsindependently selected from —NR³R⁴ and —OR³; m is 0, 1, 2, 3, 4 or 5;and j is 1 or
 2. 22. The compound of claim 21, where R¹ is Cl.
 23. Thecompound of claim 21, where R⁷ is H, 1-(4-methylpiperazinyl),morpholinyl, —NMe₂, or —CH₂(piperidinyl).
 24. The compound of claim 21,where R⁸ is Cl or Br.
 25. The compound of claim 21, where R⁹ is Cl or H.26. The compound of claim 21, where W is —COOH, —C(O)NHOCH₂—(cyclopropyl) or —C(O)NHO(CH₂)₂OH.
 27. The compound of claim 21 havingthe formula


28. The compound of claim 21 having the formula


29. The compound of claim 21 having the formula


30. The compound of claim 21 having the formula


31. The compound of claim 21 having the formula


32. The compound of claim 21 having the formula


33. The compound of claim 21 having the formula


34. The compound of claim 21 having the formula


35. The compound of claim 21 having the formula


36. The compound of claim 21 having the formula


37. A composition comprising a compound of claim 21 and apharmaceutically acceptable carrier.
 38. The prodrug of claim 21,comprising the compound of Formula II covalently coupled to an aminoacid residue.
 39. The prodrug of claim 38, wherein the amino acidresidue is valine.
 40. The prodrug of claim 21, wherein said prodrug isa phosphate ester of the compound of Formula II.
 41. The prodrug ofclaim 40, wherein said prodrug has the formula


42. A method of inhibiting MEK activity in a mammal comprisingadministrating to said mammal one or more compounds of claim 21 in anamount effective to inhibit said MEK activity.
 43. A method fortreatment of a hyperproliferative disorder in a mammal comprisingadministrating to said mammal one or more compounds of claim 21 in anamount effective to treat said hyperproliferative disorder.
 44. Acompound of the Formula III

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently selected fromhydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(n)-heterocyclyl or —NR⁴(CR⁴R⁵)n-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴ SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NRR³, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R³ ishydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an aminoacid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered saturated,unsaturated, or partially saturated heterocyclic ring, wherein any ofsaid saturated, unsaturated, or partially saturated heterocyclic ringsare optionally substituted with one or more groups independentlyselected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R′, R″ and R′″independently are hydrogen, lower alkyl, lower alkenyl, aryl orarylalkyl, R″″ is lower alkyl, lower alkenyl, aryl or arylalkyl, or anytwo of R′, R″, R′″ or R″″ together with the atom to which they areattached form a 4 to 10 membered saturated, unsaturated, or partiallysaturated heterocyclic ring, wherein any of said alkyl, alkenyl, aryl,arylalkyl saturated, unsaturated, or partially saturated heterocyclicrings are optionally substituted with one or more groups independentlyselected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁴ and R⁵ independently arehydrogen or C₁-C₆ alkyl; R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R′″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R′, —NR′C(O)NR″ R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl),—C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), or CR³OR³, whereinany of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl),—C(O)(heteroaryl), —C(O)(heterocyclyl), and CR³OR³ are optionallysubstituted with one or more groups independently selected from —NR³R⁴,—OR³, —R², C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein anyof said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR³; m is 0, 1, 2, 3, 4 or 5; and j is 1 or
 2. 45. The compound ofclaim 44, where R¹ is Cl.
 46. The compound of claim 44, where R⁷ ismethyl or benzyl.
 47. The compound of claim 44, where R⁸ is Br.
 48. Thecompound of claim 44, where R⁹ is Cl.
 49. The compound of claim 44,where W is —C(O)NHOCH₂— (cyclopropyl) or —C(O)NHO(CH₂)₂OH.
 50. Thecompound of claim 44, having the formula


51. The compound of claim 44, having the formula


52. The compound of claim 44, having the formula


53. A composition comprising a compound of claim 44 and apharmaceutically acceptable carrier.
 54. The prodrug of claim 44,comprising the compound of Formula III covalently coupled to an aminoacid residue.
 55. The prodrug of claim 54, wherein the amino acidresidue is valine.
 56. The prodrug of claim 44, wherein said prodrug isa phosphate ester of the compound of Formula III.
 57. A method ofinhibiting MEK activity in a mammal comprising administrating to saidmammal one or more compounds of claim 44 in an amount effective toinhibit said MEK activity.
 58. A method for treatment of ahyperproliferative disorder in a mammal comprising administrating tosaid mammal one or more compounds of claim 44 in an amount effective totreat said hyperproliferative disorder.
 59. A compound of the Formula IV

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, phosphate or an amino acid residue, wherein any ofsaid alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″,—NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or R³and R⁴ together with the atom to which they are attached form a 4 to 10membered saturated, unsaturated, or partially saturated heterocyclicring, wherein any of said saturated, unsaturated, or partially saturatedheterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″,—SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R′, R″ and R′″ independently are hydrogen, loweralkyl, lower alkenyl, aryl and arylalkyl, R″″ is lower alkyl, loweralkenyl, aryl and arylalkyl, or any two of R′, R″, R′″ or R″″ togetherwith the atom to which they are attached form a 4 to 10 memberedsaturated, unsaturated, or partially saturated heterocyclic ring,wherein any of said alkyl, alkenyl, aryl, arylalkyl saturated,unsaturated, or partially saturated heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl;R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R′,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl,heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³,—C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl),—C(O)(heteroaryl) and —C(O)(heterocyclyl), CR³OR³, wherein any of saidheteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³,—C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl),—C(O)(heteroaryl) and —C(O)(heterocyclyl), CR³OR³ are optionallysubstituted with one or more groups independently selected from —NR³R⁴,—OR³, —R², C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein anyof said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR³; m is 0, 1, 2, 3, 4 or 5; and j is 1 or
 2. 60. The compound ofclaim 59, where R′is 2-Cl.
 61. The compound of claim 59, where R⁷ ismethyl.
 62. The compound of claim 59, where R⁹ is F.
 63. The compound ofclaim 59, where W is —COOH or —C(O)NHO(CH₂)₂OH.
 64. The compound ofclaim 59, having the formula


65. The compound of claim 59, having the formula


66. A composition comprising a compound of claim 59 and apharmaceutically acceptable carrier.
 67. The prodrug of claim 59,comprising the compound of Formula IV covalently coupled to an aminoacid residue.
 68. The prodrug of claim 59, wherein the amino acidresidue is valine.
 69. The prodrug of claim 59, wherein said prodrug isa phosphate ester of the compound of Formula IV.
 70. A method ofinhibiting MEK activity in a mammal comprising administrating to saidmammal one or more compounds of claim 59 in an amount effective toinhibit said MEK activity.
 71. A method for treatment of ahyperproliferative disorder in a mammal comprising administrating tosaid mammal one or more compounds of claim 59 in an amount effective totreat said hyperproliferative disorder.
 72. A compound of the Formula V

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently selected fromhydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl and—NR⁴(CR⁴R⁵)_(n)-heterocyclyl, where any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; or R⁷ and R¹¹ together with the atoms to which theyare attached form a 4 to 10 membered saturated, unsaturated, orpartially saturated carbocyclic, or heterocyclic ring, wherein any ofsaid saturated, unsaturated, or partially saturated carbocyclic, orheterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″,—SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R³ is selected from hydrogen, trifluoromethyl, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, phosphate and an amino acid residue,where any of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered saturated,unsaturated, or partially saturated heterocyclic ring, wherein any ofsaid saturated, unsaturated, and partially saturated heterocyclic ringsare optionally substituted with one or more groups independentlyselected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R′, R″ and R′″independently are selected from hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl; R″″ is selected from lower alkyl, lower alkenyl,aryl and arylalkyl; or any two of R′, R″, R′″ or R″″ together with theatom to which they are attached form a 4 to 10 membered saturated,unsaturated, or partially saturated heterocyclic ring, wherein any ofsaid alkyl, alkenyl, aryl, arylalkyl saturated, unsaturated, orpartially saturated heterocyclic rings are optionally substituted withone or more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R⁴ and R⁵ independently represent hydrogen or C₁-C₆alkyl; R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; W is selected from heteroaryl, heterocyclyl,—C(O)OR³, —C(O)NR³R⁴, —C(O)NR OR, C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), C(O)(heteroaryl), —C(O)(heterocyclyl)and —CR³OR³, wherein any of said heteroaryl, heterocyclyl, —C(O)OR³,—C(O)NR³R⁴, —C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and —CR³OR³ are optionally substituted with one or more groupsindependently selected from —NR³R⁴, —OR³, —R², C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀ alkynyl, wherein any of said alkyl, alkenyl, andalkynyl portions are optionally substituted with 1 or more groupsindependently selected from —NR³R⁴ and —OR³; m is 0, 1, 2, 3, 4 or 5;and j is 1 or
 2. 73. The compound of claim 72, where R¹ is 2-Cl, 2-H, or2-F.
 74. The compound of claim 72, where R⁸ is Cl or Br.
 75. Thecompound of claim 72, where R⁹ is H, F or Cl.
 76. The compound of claim72, where W is —C(O)OH, —C(O)NHOCH₂— (cyclopropyl), —C(O)NHO(CH₂)₂OH, or—CONH(SO₂)CH₃.
 77. A composition comprising a compound of claim 72 and apharmaceutically acceptable carrier.
 78. The prodrug of claim 72,comprising the compound of Formula V covalently coupled to an amino acidresidue.
 79. The prodrug of claim 72, wherein the amino acid residue isvaline.
 80. The prodrug of claim 72, wherein said prodrug is a phosphateester of the compound of Formula V.
 81. A method of inhibiting MEKactivity in a mammal comprising administrating to said mammal one ormore compounds of 72 in an amount effective to inhibit said MEKactivity.
 82. A method for treatment of a hyperproliferative disorder ina mammal comprising administrating to said mammal one or more compoundsof claim 72 in an amount effective to treat said hyperproliferativedisorder.
 83. A compound of the Formula (I)

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein: R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR³, —C(O)R³, —C(O)OR³, NR⁴C(O)OR⁶, —OC(O)R³,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl,—NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, phosphate or an amino acid residue, wherein any ofsaid alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, C(O)OR′,—OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″,—NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or R³and R⁴ together with the atom to which they are attached form a 4 to 10membered carbocyclic, heteroaryl or heterocyclic ring, wherein any ofsaid carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″,—NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R′, R″ and R′″ independently arehydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl, and R″″ islower alkyl, lower alkenyl, aryl and arylalkyl, or any two of R′, R″,R′″ or R″″ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any ofsaid alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl ringsor heterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R⁴ and R⁵independently are hydrogen or C₁-C₆ alkyl, or R⁴ and R⁵ together withthe atom to which they are attached form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, wherein said alkyl or any of saidcarbocyclic, heteroaryl and heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR′SO₂R″″, —SO₂NR′R″, —C(O)R″″, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″,—NR′C(O)R″, —C(O)NR′R″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁶ is trifluoromethyl, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR′SO₂R″″,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″,—C(O)NR′R″, —SO₂R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl),—C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) and CR³OR³ whereinany of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(aryl),—C(O)(heteroaryl) and —C(O)(heterocyclyl), CR³OR³ are optionallysubstituted with one or more groups independently selected from —NR³R⁴,—OR³, —R², C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, wherein anyof said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR³; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2; and Y is a linker.